Increased Alanine Aminotransferase Levels Research Articles

Non-F HBV/HDV-3 coinfection is associated with severe liver disease in Western Brazilian Amazon.

The clinical outcome of hepatitis B virus (HBV) infection may be related to host and viral genetic factors, as well as to the type of infection (monoinfection and coinfection). To analyze the distribution/combination of HBV/hepatitis D virus (HDV) genotypes and the associated clinical characteristics, 409 serum samples from patients with chronic HBV (94 of them coinfected by HDV) followed at the Viral Hepatitis Referral Center of Rio Branco, Brazil were enrolled. HBV DNA and HDV RNA were amplified, respectively, by polymerase chain reaction (PCR) and nested PCR using specific primers in the PreC/C region and the S gene, and by reverse-transcription PCR and seminested PCR using specific primers in the delta antigen region and sequenced. The proportion of women (56.1%) was significantly higher than males in this cohort ( P < 0.01). Women were significantly younger (39.8 years; 8-77 years) than males (44.7 years; 12-79 years; P < 0.01). Sixty-eight (18%) patients were infected with HBV-F genotype and 264 (69.8%) with HBV/non-F genotypes. Coinfection by HDV was detected in 23.9% (94 of 409) of this population and was more frequent in male (54.2%, 51 of 94) than in female patients (44.7%, 42 of 94; P = 0.015). HDV-3 was the most prevalent (88.9%) genotype. Almost 70% of HDV-3 coinfected patients were infected with HBV/non-F genotypes. Severe liver disease was diagnosed in 41 patients, 60.9% (25 of 41) of themcoinfected with HDV. HBV/HDV coinfection was associated with male sex, age above 30 years, severe liver disease, and increased alanine aminotransferase levels. HBV/HDV-3 coinfection is associated with severe liver disease, in Rio Branco, Brazil.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms due to lamotrigine differs from that due to other drugs.

Drug-induced hypersensitivity syndrome (DIHS), also referred to as drug reaction with eosinophilia and systemic symptoms (DRESS), is a multi-organ systemic drug reaction characterized by hematological abnormalities and reactivation of human herpesvirus-6 (HHV-6). DIHS/DRESS is typically associated with a limited number of drugs, such as the anticonvulsants. Our group has treated 12 patients for DIHS/DRESS due to lamotrigine (LTG), but their presentation differed from that of patients with DIHS/DRESS caused by other drugs. The aim of the present study was to identify significant differences between DIHS/DRESS caused by LTG versus other drugs. We retrospectively reviewed data of 12 patients with DIHS/DRESS caused by LTG and 32 patients with DIHS/DRESS due to other drugs. The increase in alanine aminotransferase level was significantly milder in the LTG group than the DIHS/DRESS group due to other drugs. The percentage of atypical lymphocytes in the blood during DIHS/DRESS was lower in the LTG group. Serum levels of lactate dehydrogenase and thymus and activation-regulated chemokine were also lower in the LTG group. There were fewer DIHS/DRESS patients with HHV-6 reactivation in the LTG group than in the group treated with other drugs. Lymphocyte transformation after DIHS/DRESS onset was faster in the LTG group. The two groups did not differ with respect to the interval from first drug intake to rash, white blood cell count, blood eosinophilia or DRESS score. There were no significant histopathological differences between the two groups. The features of LTG-associated DIHS/DRESS and DIHS/DRESS due to other drugs differ.

Abdominal Travmada Mortaliteyi Etkileyen Risk Faktörlerinin Analizi

The present study aims to analyze blunt and penetrating abdominal traumas that were evaluated in our emergency department, the treatment approaches and risk factors of mortality. Six hundred and sixty-four patients were admitted to our emergency department for surgical evaluation for trauma between January 2009 and April 2019. After the exclusion of dead on arrival, patients with missing data and patients without abdominal trauma were excluded from this study. Hundred and thirteen patients with abdominal trauma admitted to our department were evaluated in this study. Demographic, clinical, prognostic and mortality related factors were retrospectively analyzed. The mean age of the patients was 36.08±16.1 years. There were 90 male patients. Eighty patients (70.8%) had blunt abdominal trauma (BAT). Twenty-eight patients (24.7%) had isolated liver and two patients (1.7%) had isolated spleen injury. Combined liver and spleen injury was found in two patients (1.7%). Twenty-two (19.4%) patients had mortality. Causes of mortality were an irreversible hemorrhagic shock (40.9%) and central nervous system (13.6%) injuries. BAT was the main mechanism of injury in patients with mortality (86.4% versus 67%; p<0.001). The frequency of retroperitoneal injury was significantly higher in patients with mortality (50% versus 16.5%, p<0.001). The frequency of extra-abdominal injury in patients with mortality was higher (68.1% versus 49.4%; p=0.047). Mean arterial pressure at admission was found to be significantly lower in patients with mortality (67±26.8 mmHg versus 84.3±17 mmHg; p=0.02). The number of packed erythrocytes transfused in patients with mortality was higher (8.8±8.6 versus 3.3±5.9 units; p=0.047). Mean international normalized ratio (INR) was significantly higher in patients with mortality (4.3±7.1 versus 2.7±4; p=0.016). Mean lactate dehydrogenase level was higher in patients with mortality (1685.7±333.8 versus 675.8±565.3 IU/mL; p<0.001). Mean alanine aminotransferase (ALT) was significantly higher in patients with mortality (430±619 versus 244±448 IU/mL; p<0.001). Mean alkaline phosphatase (ALP) level in patients with mortality was higher (76.9±72.8 versus 67.3±27.8 IU/mL; p=0.003). The presence of retroperitoneal injury and ALT >516 IU/mL were independent risk factors o mortality. We have found certain laboratory variables to increase in patients with mortality. These are related to the severity of trauma. Retroperitoneal injury and increased ALT levels being risk factors of mortality is the most important finding of this study. Our results can guide other centers in the evaluation of trauma patients, and high-risk groups can be identified.

Absence of HBV Reactivation in Patients With Resolved HBV Infection Following DAA Therapy for Hepatitis C: A 1-Year Follow-up Study.

BackgroundPatients with chronic hepatitis C virus (HCV) infection and active or previous hepatitis B virus (HBV) are at risk of HBV reactivation (HBV-R) during direct-acting antiviral (DAA) therapy. Recent reports suggest that HBV-R may even occur several months after completion of DAA therapy. The aim of this study was to assess the risk of HBV-R in patients with resolved HBV after successful DAA therapy during long-term follow-up (FU).MethodsAmong 848 patients treated for chronic HCV, all patients with resolved HBV and long-term FU data were eligible for inclusion. Patients were HBV DNA/hepatitis B surface antigen (HBsAg)–negative at the end of therapy (EOT) and were followed for up to 52 weeks thereafter. Patients underwent regular alanine transaminase (ALT) testing, and additional HBV DNA/HBsAg testing was performed at FU week 12, end of FU, and in case of an ALT increase above the upper limit of normal (>ULN).ResultsA total of 108 patients were followed up for a mean (range) of 41.5 (24–52) weeks after EOT. None of the patients experienced reverse HBsAg seroconversion or reappearance of HBV DNA. One patient received a liver transplantation; 1 patient was diagnosed with de novo hepatocellular carcinoma, and 2 patients died. Eighteen patients (16.7%) had increased ALT levels (grade 0/1). Of those, the majority were male (72.2%) and significantly more patients had cirrhosis (66.7% vs 36.2%, P = .015) or received ribavirin as part of their treatment regimen (86.7% vs 46.8%, P = .041). None of these were associated with HBV-R.ConclusionsOur results indicate that the risk of HBV-R in patients with resolved HBV treated with DAAs for HCV is low during long-term follow-up.

Sorafenib with or without concurrent transarterial chemoembolization in patients with advanced hepatocellular carcinoma: The phase III STAH trial

Sorafenib is first-line standard of care for patients with advanced hepatocellular carcinoma (HCC), yet it confers limited survival benefit. Therefore, we aimed to compare clinical outcomes of sorafenib combined with concurrent conventional transarterial chemoembolization (cTACE) vs. sorafenib alone in patients with advanced HCC. In this investigator-initiated, multicenter, phase III trial, patients were randomized to receive sorafenib alone (Arm S, n = 169) or in combination with cTACE on demand (Arm C, n = 170). Sorafenib was started within 3 days and cTACE within 7-21 days of randomization. The primary endpoint was overall survival (OS). For Arms C and S, the median OS was 12.8 vs. 10.8 months (hazard ratio [HR] 0.91; 90% CI 0.69-1.21; p = 0.290); median time to progression, 5.3 vs. 3.5 months (HR 0.67; 90% CI 0.53-0.85; p = 0.003); median progression-free survival, 5.2 vs. 3.6 months (HR 0.73; 90% CI 0.59-0.91; p = 0.01); and tumor response rate, 60.6% vs. 47.3% (p = 0.005). For Arms C and S, serious (grade ≥3) adverse events occurred in 33.3% vs. 19.8% (p = 0.006) of patients and included increased alanine aminotransferase levels (20.3% vs. 3.6%), hyperbilirubinemia (11.8% vs. 3.0%), ascites (11.8% vs. 4.2%), thrombocytopenia (7.2% vs. 1.2%), anorexia (7.2% vs. 1.2%), and hand-foot skin reaction (10.5% vs. 11.4%). A post hoc subgroup analysis compared OS in Arm C patients (46.4%) receiving ≥2 cTACE sessions to Arm S patients (18.6 vs. 10.8 months; HR 0.58; 95% CI 0.40-0.82; p = 0.006). Compared with sorafenib alone, sorafenib combined with cTACE did not improve OS in patients with advanced HCC. However, sorafenib combined with cTACE significantly improved time to progression, progression-free survival, and tumor response rate. Sorafenib alone remains the first-line standard of care for patients with advanced HCC. For patients with advanced hepatocellular carcinoma requiring sorafenib therapy, co-administration with conventional transarterial chemoembolization did not improve overall survival compared to sorafenib alone. Therefore, sorafenib alone remains the first-line standard of care for patients with advanced hepatocellular carcinoma. Clinical Trial Number: NCT01829035.

Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-κB pathway.

Fenvalerate (FEN), a mainstream pyrethroid pesticide, was initially recommended as a low-toxicity agent for controlling agricultural and domestic pests. Despite the widespread use of FEN worldwide, little data are available on FEN-induced hepatic lesions and molecular mechanisms. In the present study, we first performed an occupational cross-sectional study on FEN factory workers and found that the levels of serum alanine aminotransferase (ALT) and total antioxidant capacity increased, whereas malondialdehyde decreased in laborers in the working areas where the levels of airborne FEN were much higher compared with the office area. The results were then confirmed by animal experiments that abnormal hepatic histology, increased ALT level, and compromised hepatic oxidative capability were observed in rats exposed to a high concentration of FEN. Furthermore, the bioinformatics analysis of gene microarray in rat liver tissue showed that FEN significantly changed the expressions of genes related to the regulation of intracellular calcium ion homeostasis and the calcium signal pathway. Finally, the functional experiments in Buffalo rat liver (BRL) cells demonstrated that FEN first activated ERK MAPK, followed by IKK and NF-κB, which triggered the transcription of genes responsible for accelerating an overload of intracellular calcium ions, prompted reactive oxygen species generation in the mitochondria, and finally, induced hepatic cellular apoptosis. The calcium signaling pathway and in particular, an overload of intracellular calcium play a critical role in this pathophysiological process via the ERK/IKK/NF-κB pathway. Our study furthers the understanding of the mechanism of FEN-induced hepatic injuries and may have implications in the prevention and control of liver diseases induced by environmental pesticides.-Qiu, L.-L., Wang, C., Yao, S., Li, N., Hu, Y., Yu, Y., Xia, R., Zhu, J., Ji, M., Zhang, Z., Wang S.-L. Fenvalerate induces oxidative hepatic lesions through an overload of intracellular calcium triggered by the ERK/IKK/NF-κB pathway.

Laboratory Evaluation and Serum Level of Phenobarbital Administered by Different Pathways in Dogs

Background: Anticonvulsants are widely used in the treatment of small animals for the remission of isolated seizures and recurrent seizures in epilepsy, including tonic-clonic seizures and in status epileticus. Phenobarbital is the drug of choice for the management of epileptic seizures, it is considered very effective, safe, low cost and with few side effects. Several routes of administration may be used, with the oral, intravenous and intramuscular routes being the most common, with rectal and nasal routes being the least common. Materials, Methods &amp; Results: Twenty mongrel dogs were used in the present study (aged 1 to 6-year-old, males and females, weighing 6.0 to 17.0 kg). The patients were previously evaluated via physical examination, temperature, respiratory and heart rate, laboratory tests (erythrogram and leukogram), and serum biochemistry by analyzing the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (FA), and gamma-glutamyltransferase (GGT). Four experimental groups were established with five animals in each group: animals receiving intramuscular injections of phenobarbital (VIM), animals receiving nasal administration of phenobarbital (VN), animals receiving rectal administration of phenobarbital (VR), and animals receiving oral administration of phenobarbital (VO). Phenobarbital was administered every 12 h for 15 days. To determine the serum level of phenobarbital, 5 mL of jugular vein blood was collected in vacuum tubes for evaluation via hemogram. The serum level was determined after 15 days of continuous administration of phenobarbital, as stable phenobarbital serum levels can only be achieved from 10 to 15 days after the first administration. For the serum biochemistry evaluation, 10 mL of blood from the jugular vein was collected using vacuum syringes for assessing ALT, AST, GGT, and FA levels. Statistical analyses were performed with contrasted variation analysis using the Tukey method and paired t-test for comparison of time points. The level of significance was determined to be 5%. There was a significant difference (P &lt; 0.05) among drug administration routes, and among the levels of AST and AF enzymes after the first administration of phenobarbital via the nasal and intramuscular routes. Based on the results, it was concluded that hepatic alterations secondary to the use of phenobarbital for 15 days may occur with a low incidence. The phenobarbital serum concentration in dogs varied when administered via nasal, rectal, and intramuscular routes, but was stable when administered orally.Discussion: The current results are consistent with those of previous studies, indicating that the chronic use of phenobarbital causes an increase in the serum levels of ALT and FA enzymes. It was found that phenobarbital serum levels varied greatly, particularly following nasal, rectal, and intramuscular administration. In the present study, serum phenobarbital levels were within the normal range when administered via the intramuscular, nasal, rectal, and oral routes. This result is inconsistent with that of previous studies where the serum levels were below the normal range following oral administration of phenobarbital. The serum concentration, rather than clinical criteria, should be used as a guide for treatment modification, as the distribution of this drug varies greatly among animals.

Increased Hepatotoxicity Associated with Sequential Immune Checkpoint Inhibitor and Crizotinib Therapy in Patients with Non–Small Cell Lung Cancer

IntroductionImmune checkpoint inhibitors (ICIs) are standard therapies in advanced NSCLC. Although genotype-directed tyrosine kinase inhibitors represent the standard of care for subsets of oncogene-driven NSCLC, patients may receive ICIs during their disease course. The impact of sequential ICI and tyrosine kinase inhibitor therapy on the risk of hepatotoxicity has not been described. MethodsPatients with advanced ALK receptor tyrosine kinase (ALK)-driven, ROS1-driven, or MET proto-oncogene, receptor tyrosine kinase (MET)-driven NSCLC treated with crizotinib, with or without preceding ICI therapy, were identified. The cumulative incidences of crizotinib-associated grade 3 or higher increases in transaminase level (per the Common Terminology Criteria for Adverse Events, version 4.0) were compared. ResultsWe identified 453 patients who had NSCLC with an oncogenic alteration in ALK receptor tyrosine kinase gene (ALK), ROS1, or MET proto-oncogene, receptor tyrosine kinase gene (MET) and were treated with crizotinib (11 with and 442 without prior ICI therapy). Among the 11 patients treated with an ICI followed by crizotinib, five (cumulative incidence 45.5% [95% confidence interval (CI): 14.9–72.2]) experienced development of a grade 3 or 4 increase in alanine transaminase level and four (cumulative incidence 36.4% [95% CI: 10.0–64.2]) experienced development of a grade 3 or 4 increase in aspartate transaminase level. In comparison, among the 442 patients who received crizotinib only, a grade 3 or 4 increase in alanine transaminase level occurred in 34 patients (cumulative incidence 8.1% [95% CI: 5.7–11.0, p < 0.0001]) and a grade 3 or 4 increase in aspartate transaminase level occurred in 14 (cumulative incidence 3.4% [95% CI: 1.9–5.5, p < 0.0001]). There were no grade 5 transaminitis events. All cases of hepatotoxicity after sequential ICI and crizotinib use were reversible and nonfatal, and no case met the Hy’s law criteria. ConclusionsSequential ICI and crizotinib treatment is associated with a significantly increased risk of hepatotoxicity. Careful consideration and monitoring for hepatotoxicity may be warranted in patients treated with crizotinib after ICI therapy.

Essential oils of green cumin and chamomile partially protect against acute acetaminophen hepatotoxicity in rats.

Essential oils of green cumin (Cuminum cyminum) and chamomile (Chamomilla recutita) have antioxidant and anti-inflammatory effects. Acetaminophen, N-acetyl-p-amino-phenol, is an over-the-counter analgesic and antipyretic. Despite being safe at therapeutic doses, acetaminophen overdose is a leading cause of acute liver failure. This study aimed to compare the possible protective effects of cumin and chamomile essential oils against acute acetaminophen hepatotoxicity in male rats. Cumin oil (400 mg/kg) and chamomile oil (250 mg/kg) were orally administered for 2 weeks prior to a single acetaminophen dose (1g/kg). Serum liver function enzymes, oxidative stress markers in the liver and histopathological features were evaluated. Acetaminophen caused marked damage to hepatocytes evidenced by a significant rise in the levels of liver function enzymes, including alanine aminotransferase and aspartate aminotransferase, and disruption to the liver antioxidant protective system. Whereas the cumin oil normalized acetaminophen-induced liver enzymes elevation, the chamomile oil slightly attenuated the increase in alanine aminotransferase levels in acetaminophen-intoxicated rats. The Chamomile oil moderately ameliorated glutathione depletion and the decrease in superoxide dismutase activity in the liver of acetaminophen-administered rats. The Cumin oil preserved the liver structure to a greater extent than chamomile oil in acetaminophen-intoxicated rats. Essential oils of cumin and chamomile partially counteracted acute acetaminophen hepatotoxicity.

Assessment of cyclohexanone toxicity in inhalation-exposed F344 rats and B6C3F1 mice: applications in occupational health

Background: Cyclohexanone is a chemical used in various industries and many workers are exposed to it. Therefore, in this study, we determined the toxicity of cyclohexanone in inhalation-exposed F344 rats and B6C3F1 mice, so as to apply the findings in hazard and risk assessments.Methods: Ten male and 10 female rats and mice per test group were exposed to cyclohexanone vapors at 0, 100, 250, and 625 ppm concentrations for 6 h per day, 5 d per week, and for 13 weeks. All rats and mice were killed after the exposure period. Clinical signs, body weight, feed intake, and ophthalmoscopy findings were recorded during the exposure period, and hematology, blood biochemistry, organ weights, gross findings, and histopathology were evaluated thereafter.Results: The following findings were noted in cyclohexanone-exposed F344 rats: increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, increased liver weight, and bile duct hyperplasia in the males exposed to 250 and 625 ppm cyclohexanone, increased ALT levels and bile duct hyperplasia in the females exposed to 625 ppm cyclohexanone, and increased blood urea nitrogen (BUN) and tubular basophilia in the renal cortex in the males exposed to 625 ppm cyclohexanone. On the other hand, B6C3F1 mice exposed to cyclohexanone showed no obvious exposure-related effects.Conclusion: Based on the findings, the no-observed-adverse-effect level (NOAEL) was determined to be 100 ppm in F344 rats and >625 ppm in B6C3F1 mice. Therefore, 2 ppm was revealed as the derived no-effect level (DNEL) for cyclohexanone.

Association between serum S100A9 levels and liver necroinflammation in chronic hepatitis B

BackgroundS100A9 protein, which is recently classified as a novel damage associated molecular pattern, is released from stressed cells undergoing necrosis or secreted by living cells undergoing a stress that act as endogenous danger signal associated with infection, tissue damage and cancer. Here, we evaluated the relationship of serum S100A9 with viral replication and liver necroinflammation in patients with chronic hepatitis B (CHB) infection.MethodsA total of one hundred and eighty-three recruited patients with CHB infection underwent liver biopsy for grading of necroinflammation (G) and staging of fibrosis (S). Forty-nine healthy individuals were included as healthy controls (HCs). Serum S100A9 levels were determined by enzyme-linked immunosorbent assay. Correlations of serum S100A9 with viral replication and liver necroinflammation were analyzed. The receiver operating characteristic curve was used to assess the discriminating power of serum S100A9 to grade liver necroinflammation (G). Liver normal L02 cells were transfected with a HBV plasmid, and S100A9 levels were determined.ResultsSerum S100A9 levels were increased in CHB patients compared to HCs. Intrahepatic immunoreactivity for S100A9 was enhanced in liver sample from CHB patients. Infection of HBV also resulted in an elevated S100A9 expression in L02 cells. Serum S100A9 was correlated with the serum HBV DNA levels. CHB patients with moderate-to-severe liver necroinflammation (G ≥ 2) showed significantly higher serum S100A9 levels than those without or with mild necroinflammation (G < 2). In patients with normal ALT levels, the area under the curve (AUC) of S100A9 for discriminating patients with moderate-to-severe necroinflammation (G ≥ 2) was 0.791 [95% confidence interval (CI), 0.670–0.913] with 91.7% sensitivity, 65.0% specificity and 78.3% accuracy. In patients with an alanine aminotransferase (ALT) < 2 upper limit of normal, the AUC of S100A9 for discriminating patients with moderate-to-severe necroinflammation (G ≥ 2) was 0.826 (95% CI, 0.729–0.923) with 87.9% sensitivity, 72.5% specificity and 80.2% accuracy.ConclusionsHBV infection may enhance S100A9 expression. Serum S100A9 levels are correlated with viral load. Serum S100A9 has potential to discriminate the grades of liver necroinflammation, particularly in CHB patients with normal or mildly increased ALT levels.

Ethyl pyruvate ameliorates hepatic injury following blunt chest trauma and hemorrhagic shock by reducing local inflammation, NF-kappaB activation and HMGB1 release.

BackgroundThe treatment of patients with multiple trauma including blunt chest/thoracic trauma (TxT) and hemorrhagic shock (H) is still challenging. Numerous studies show detrimental consequences of TxT and HS resulting in strong inflammatory changes, organ injury and mortality. Additionally, the reperfusion (R) phase plays a key role in triggering inflammation and worsening outcome. Ethyl pyruvate (EP), a stable lipophilic ester, has anti-inflammatory properties. Here, the influence of EP on the inflammatory reaction and liver injury in a double hit model of TxT and H/R in rats was explored.MethodsFemale Lewis rats were subjected to TxT followed by hemorrhage/H (60 min, 35±3 mm Hg) and resuscitation/R (TxT+H/R). Reperfusion was performed by either Ringer`s lactated solution (RL) alone or RL supplemented with EP (50 mg/kg). Sham animals underwent all surgical procedures without TxT+H/R. After 2h, blood and liver tissue were collected for analyses, and survival was assessed after 24h.ResultsResuscitation with EP significantly improved haemoglobin levels and base excess recovery compared with controls after TxT+H/R, respectively (p<0.05). TxT+H/R-induced significant increase in alanine aminotransferase levels and liver injury were attenuated by EP compared with controls (p<0.05). Local inflammation as shown by increased gene expression of IL-6 and ICAM-1, enhanced ICAM-1 and HMGB1 protein expression and infiltration of the liver with neutrophils were also significantly attenuated by EP compared with controls after TxT+H/R (p<0.05). EP significantly reduced TxT+H/R-induced p65 activation in liver tissue. Survival rates improved by EP from 50% to 70% after TxT+H/R.ConclusionsThese data support the concept that the pronounced local pro-inflammatory response in the liver after blunt chest trauma and hemorrhagic shock is associated with NF-κB. In particular, the beneficial anti-inflammatory effects of ethyl pyruvate seem to be regulated by the HMGB1/NF-κB axis in the liver, thereby, restraining inflammatory responses and liver injury after double hit trauma in the rat.

Tissue influx of neutrophils and monocytes is delayed during development of trovafloxacin-induced tumor necrosis factor-dependent liver injury in mice.

Idiosyncratic drug-induced liver injury (iDILI) has a poorly understood pathogenesis. However, iDILI is often associated with inflammatory stress signals in human patients as well as animal models. Tumor necrosis factor (TNF) and neutrophils play a key role in onset of trovafloxacin (TVX)-induced iDILI, but the exact role of neutrophils and other leukocytes remains to be defined. We therefore set out to study the kinetics of immunological changes during the development of TVX-induced iDILI in the established murine model of acute liver injury induced by administration of TVX and TNF. Initially, TNF stimulated the appearance of leukocytes, in particular neutrophils, into the liver of TVX-treated mice, but even more so in control mice treated with the non-DILI inducing analogue levofloxacin (LVX) or saline as vehicle (Veh). This difference was apparent at 2hours after TNF administration, but at 4hours, the relative neutrophil amounts were reduced again in Veh- and LVX-treated mice whereas the amounts in TVX-treated mice remained at the same increased level as at 2hours. The influx of monocytes/macrophages, which was unaffected in Veh- and LVX-treated mice was markedly reduced or even absent in TVX-treated mice. Unlike controls, mice receiving TVX + TNF display severe hepatotoxicity with clear pathology and apoptosis, coagulated hepatic vessels and increased alanine aminotransferase levels and interleukin 6/10 ratios. Findings indicate that TVX delays the acute influx of neutrophils and monocytes/macrophages. Considering their known anti-inflammatory functions, the disruption of influx of these innate immune cells may hamper the resolution of initial cytotoxic effects of TVX and thus contribute to liver injury development.

Targeted mRNA Therapy for Ornithine Transcarbamylase Deficiency.

We describe a novel, two-nanoparticle mRNA delivery system and show that it is highly effective as a means of intracellular enzyme replacement therapy (i-ERT) using a murine model of ornithine transcarbamylase deficiency (OTCD). Our Hybrid mRNA Technology delivery system (HMT) comprises an inert lipid nanoparticle that protects the mRNA from nucleases in the blood as it distributes to the liver and a polymer micelle that targets hepatocytes and triggers endosomal release of mRNA. This results in high-level synthesis of the desired protein specifically in the liver. HMT delivery of human OTC mRNA normalizes plasma ammonia and urinary orotic acid levels, and leads to a prolonged survival benefit in the murine OTCD model. HMT represents a unique, non-viral mRNA delivery method that allows multi-dose, systemic administration for treatment of single-gene inherited metabolic diseases.

Omega-loop gastric bypass is more effective for weight loss but negatively impacts liver enzymes: a registry-based comprehensive first-year analysis

BackgroundThe impact of omega-loop gastric bypass (OLGB) on weight loss and liver enzymes remains inconclusive. ObjectiveThe aim of this study was to compare the impact of sleeve gastrectomy (SG), Roux-en-Y gastric bypass (RYGB), and OLGB on weight loss and liver enzyme levels. SettingNational Bariatric Surgery Registry. MethodsThe study included 10,675 cases of SG, 1590 cases of RYGB, and 469 cases of OLGB that had available baseline and 1-year (12 ± 2 mo) follow-up data. ResultsThe highest percentage of excess weight loss was achieved by the OLGB group (84.5% ± 26.7%), followed by the SG (78.5% ± 26.0%) and RYGB (72.0% ± 26.5%) groups (P<.05). The data show that 10% of OLGB cases, 5.2% of RYGB cases, and 1.9% of SG cases (P<.001) had increases in alanine aminotransferase levels, from a normal baseline mean of 23.9 ± 7.5 U/L to an abnormal mean of 64.8.7 ± 66.0 U/L, at follow-up. Similar trends were observed for aspartate aminotransferase and alkaline phosphatase. A regression analysis showed that OLGB was a predictive risk factor for normal baseline alanine aminotransferase levels becoming abnormal postoperatively compared with SG (odds ratio [OR] = 5.65) or RYGB (OR = 2.08) (P<.001). Similarly, OLGB was a predictive risk factor for baseline aspartate aminotransferase and alkaline phosphatase levels becoming abnormal postoperatively. Female sex was the only other meaningful predictive risk of alanine aminotransferase (OR = 2.45) and aspartate aminotransferase (OR = 1.82) becoming abnormal postoperatively. ConclusionThis study confirmed the strengths of OLGB weight loss outcomes but also demonstrated its negative impact on liver enzymes. Thus, patients and caregivers should be informed of the risks, and close follow-up is warranted.

Gugulipid causes hypercholesterolemia leading to endothelial dysfunction, increased atherosclerosis, and premature death by ischemic heart disease in male mice.

For proper cholesterol metabolism, normal expression and function of scavenger receptor class B type I (SR-BI), a high-density lipoprotein (HDL) receptor, is required. Among the factors that regulate overall cholesterol homeostasis and HDL metabolism, the nuclear farnesoid X receptor plays an important role. Guggulsterone, a bioactive compound present in the natural product gugulipid, is an antagonist of this receptor. This natural product is widely used globally as a natural lipid-lowering agent, although its anti-atherogenic cardiovascular benefit in animal models or humans is unknown. The aim of this study was to determine the effects of gugulipid on cholesterol homeostasis and development of mild and severe atherosclerosis in male mice. For this purpose, we evaluated the impact of gugulipid treatment on liver histology, plasma lipoprotein cholesterol, endothelial function, and development of atherosclerosis and/or ischemic heart disease in wild-type mice; apolipoprotein E knockout mice, a model of atherosclerosis without ischemic complications; and SR-B1 knockout and atherogenic–diet-fed apolipoprotein E hypomorphic (SR-BI KO/ApoER61h/h) mice, a model of lethal ischemic heart disease due to severe atherosclerosis. Gugulipid administration was associated with histological abnormalities in liver, increased alanine aminotransferase levels, lower hepatic SR-BI content, hypercholesterolemia due to increased HDL cholesterol levels, endothelial dysfunction, enhanced atherosclerosis, and accelerated death in animals with severe ischemic heart disease. In conclusion, our data show important adverse effects of gugulipid intake on HDL metabolism and atherosclerosis in male mice, suggesting potential and unknown deleterious effects on cardiovascular health in humans. In addition, these findings reemphasize the need for rigorous preclinical and clinical studies to provide guidance on the consumption of natural products and regulation of their use in the general population.

Health-related Quality of Life in Pediatric Patients With Chronic Hepatitis B Living in the United States and Canada.

The aim of the study was to determine whether selected sociodemographic and hepatitis B virus (HBV)-specific clinical factors are associated with health-related quality of life (HRQoL) among pediatric patients chronically infected with HBV. Children with chronic HBV enrolled in the Hepatitis B Research Network completed the Child Health Questionnaire at study entry. Caregivers of children 5 to <10 years completed the parent-reported form (CHQ-Parent Report Form); youth 10 to <18 years completed the child-reported CHQ-Child Report Form. We examined univariable associations of the Child Health Questionnaire scores with selected independent variables: sex, adoption status, maternal education, alanine aminotransferase (U/L), aspartate aminotransferase-to-platelet ratio index, and HBV-specific symptom count. A total of 244 participants (83 young children 5-<10 years, 161 youth 10-<18 years) were included, all HBV treatment-naïve. Among young children, increased alanine aminotransferase level was negatively associated with CHQ-Parent Report Form psychosocial summary t score (r = -0.28, P = 0.01). No other subscale comparisons for young children were statistically significant. Among youth, adoption was associated with better physical functioning and general health (P < 0.01). Higher maternal education was associated with better role/functioning-physical and -emotional scores (P < 0.05). Maternal education and adoption status were linked with adoption associated with higher maternal education. Increased symptom count in youth was associated with worse HRQoL in subscales measuring bodily pain, behavior, mental health, and self-esteem (P < 0.01). Although overall HRQoL is preserved in children with chronic HBV, some sociodemographic and HBV-related clinical factors were associated with impaired HRQoL in our pediatric patients at baseline. Measurement of HRQoL can focus resources on education and psychosocial support in children and families most in need.

Telbivudine treatment started in early and middle pregnancy completely blocks HBV vertical transmission

BackgroundTo evaluate the efficacy and safety of treating HBV-positive mothers with telbivudine in early and middle pregnancy to prevent mother-to-infant HBV transmission.MethodsThe subject population comprised pregnant women with chronic hepatitis B (CHB; n = 188) from January 2013 to June 2015, with HBV DNA ≥1.0 × 107copies/mL and increased alanine aminotransferase levels. Groups A (n = 62) and B (n = 61) were treated with telbivudine starting at 12 weeks or 20–28 weeks after gestation, respectively. Telbivudine was discontinued at postpartum 12 weeks. Group C (n = 65) received no antiviral. All infants were vaccinated with hepatitis B immunoglobulin (200 IU) and HBV vaccine (20 with hepatitis B The maternal HBV DNA levels of the groups were compared. Mother-to-infant transmission of HBV was indicated by the presence of HBsAg in infants 7 months after birth.ResultsBefore treatment, the HBV DNA levels of the 3 groups were similar. Before delivery and 12 weeks after delivery, the HBV DNA levels of groups A and B were similar, but both were significantly lower than that of group C (P < 0.01, all). No infants in groups A and B were HBsAg-positive, but the infection rate of group C was 18.4% (P < 0.01). The HBV infection rate of infants was positively associated with the HBV DNA levels of the pregnant mothers.ConclusionAdministration of telbivudine to HBV-infected mothers, started during early and middle pregnancy, completely blocked mother-to-infant HBV transmission.Trial registrationThe study was registered retrospectively on Janurary 25 in 2016 at Chinese Clinical Trial Registry (ChiCTR-OPC-16007899).

Factors Associated With Persistent Increase in Level of Alanine Aminotransferase in Patients With Chronic Hepatitis B Receiving Oral Antiviral Therapy.

Despite complete suppression of viral DNA with antiviral agents, in some patients with chronic hepatitis B (CHB), serum levels of alanine aminotransferase (ALT) do not normalize. We investigated factors associated with persistent increases in ALT level in patients with CHB given long-term tenofovir disoproxil fumarate. We analyzed data from 471 hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with CHB participating in 2 phase 3 trials. We identified patients with an increased level of ALT (above the upper limit of normal range) after 5 years (240 weeks) of tenofovir disoproxil fumarate therapy. We analyzed findings from liver biopsy specimens collected from 467 patients (99%) at baseline and 339 patients (72%) at year 5 of treatment; biopsy specimens were evaluated by an independent pathologist. We performed stepwise, forward, multivariate regression analyses of specified baseline characteristics and on-treatment response parameters to identify factors associated with persistent increases in ALT level. Of the 471 patients, 87 (18%) still had an increased ALT level at year 5 of treatment. Factors associated significantly with a persistent increase in ALT level were a steatosis score of 5% or greater (grade 1 or more) at baseline (odds ratio [OR], 2.236; 95% confidence interval [CI], 1.031-4.852; P= .042) and at year 5 (OR, 3.392; 95% CI, 1.560 ≥ 7.375; P= .002), HBeAg seropositivity at baseline (OR, 3.297; 95% CI, 1.653-6.576; P < .001), and age 40 years or older (OR, 2.099; 95% CI, 1.014-4.342; P= .046). Of the 42 HBeAg-positive patients with steatosis at baseline, 21 (50%) had an increased ALT level at year 5 of treatment. Patients with persistent increases in ALT level were more likely to have an increase in steatosis at year 5 than those with a normal ALT level. HBeAg seropositivity and hepatic steatosis contribute to persistent increases in ALT level in patients with CHB receiving suppressive antiviral treatment. ClinicalTrials.gov registration numbers: NCT00117676 and NCT00116805.

Chronic hepatitis B in children: Therapeutic challenges and perspectives

Chronic hepatitis B virus (HBV) infection and HBV-related hepatitis in children remains an unmet medical need, as current treatments are only partially effective, and only in a limited number of affected children. So-called "immunotolerant" children have not shown increased serological responses to available treatments. In cases involving more active disease, serological response has only been obtained in approximately one-third of patients when using interferon, while other cases exhibited virological response solely under continuous treatment with nucleoside analogs. Guidelines have recently been established to aid pediatricians in effectively managing this condition. With the available medications, no treatment is so far indicated for immunotolerant children, but only for cases presenting increased alanine aminotransferase levels to over 1.5-2 times the upper limit of normal for over 6 months, and without spontaneous HB envelope antigen to antibody seroconversion. The therapeutic arsenal approved by the Food and Drugs Administration and European Medicines Agency for children remains limited because of the lack of large-scale clinical trials validating treatments already approved for the adult population. Yet, the recent discovery of a specific HBV-cell surface receptor, NTCP, allows for new treatment perspectives regarding the future.