Elevated Alanine Aminotransferase Research Articles

Liver enzyme profiles after initiating biological treatment in children with inflammatory bowel diseases.

Biological treatments (BTs) are essential in managing pediatric inflammatory bowel diseases (PIBDs). Elevated liver enzymes sometimes succeed BT, yet elucidating studies are scarce. We addressed liver biochemistry after introducing BT and searched for their determinants. We identified PIBD patients receiving infliximab, adalimumab, vedolizumab, or ustekinumab at the Children's Hospital, University of Helsinki, Finland, in 2000-2023, and followed their alanine transaminase (ALT) and γ-glutamyl transpeptidase (GT) levels for 24 months. ALT was categorized based on the age- and sex-specific upper limit of normal. We disregarded 46 patients with underlying primary sclerosing cholangitis with/without autoimmune hepatitis (AIH), pretreatment AIH diagnosis, and elevated liver enzymes at the beginning of BT from the analyses. Of 618 BT episodes in 403 patients, 22.2% exhibited increased ALT or GT (ALT in 117, GT in 4, and both ALT/GT in 16 episodes). Of all ALT elevations (n = 133), 41.4% occurred within the first 3 months. ALT elevation was more common after infliximab (representing 59.5% of BTs) than other BTs (25.9% vs. 14.2%, adjusted odds ratio [OR]: 2.41, 95% confidence interval [CI]: 1.23-4.72). AIH followed 1.5% (n = 9) of BT episodes. Ninety-five percent of ALT elevations resolved within 6 months. Antibiotic exposure (particularly to metronidazole) was associated with ALT elevation in general (adjusted OR: 5.76, 95% CI: 2.40-13.9) and short disease duration before starting BT with notable ALT elevation (adjusted OR: 1.10, 95% CI: 1.01-1.22). Benign ALT elevation is common within 3 months after starting BT (especially infliximab) and scarcely led to cessation of the treatment. AIH is a rare finding during the first year of BT.

Guava polysaccharides attenuate high fat and STZ-induced hyperglycemia by regulating gut microbiota and arachidonic acid metabolism

This study investigated the hypoglycemic mechanism of guava polysaccharides (GP) through the gut microbiota (GM) and related metabolites. Our findings demonstrated that GP significantly mitigated high-fat diet- and streptozotocin-induced hyperglycemia, insulin resistance, hyperlipidemia, elevated alanine aminotransferase, high hepatic inflammation levels, and prevented pancreatic atrophy and hepatomegaly. Interestingly, the benefits of GP were attributed to alterations in the GM. GP decreased the ratio of Firmicutes to Bacteroidetes, significantly inhibiting deleterious bacteria, including Uncultured_f_Desulfovibrionaceae, Bilophila, and Desulfovibrio, while promoting the proliferation of probiotic Bifidobacterium and Bacteroides. In addition, GP promoted the generation of short-chain fatty acids. Notably, the arachidonic acid (AA) metabolism pathway was enriched in liver metabolites. GP significantly elevated hepatic AA and 15-hydroxyeicosatetraenoic acid, while reducing prostaglandin E2 and 5- and 12-hydroxyeicosatetraenoic acid. This modulation is accompanied by the downregulation of hepatic cyclooxygenase-1, 12-lipoxygenase, P38, and c-Jun N-terminal kinase mRNA expression, and the upregulation of cytochrome P4502J5 and insulin receptor substrate 1/2 mRNA expression. However, GP antibiotic treatment did not induce significant alterations in FBG and AA levels or gene expression. Overall, our findings suggest that the hypoglycemic effect of GP may be intricately linked to alterations in AA metabolism, which depends on the GM.

Comparative efficacy and safety of first-line tyrosine kinase inhibitors in chronic myeloid leukemia: a systematic review and network meta-analysis.

Tyrosine kinase inhibitors (TKIs) have become the preferred drugs for the treatment of chronic phase (CP) chronic myeloid leukemia (CML). This study aims to compare the safety and efficacy of different TKIs as first-line treatments for CML using network meta-analysis (NMA), providing a basis for the precise clinical use of TKIs. A systematic search was conducted on PubMed, Cochrane Library, Embase, China National knowledge Infrastructure (CNKI), Wanfang, Chinese Science and Technology Periodical Databases (VIP), SinoMed and ClinicalTrials.gov to include RCTs that compared the different TKIs as first line treatment for CML. The search timeline was from inception to 21 July 2023. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and the frequentist NMA methods, the efficacy and safety of different TKIs were compared, including the rates of major molecular response (MMR), complete cytogenetic response (CCyR), all grade adverse events, grade 3 or higher hematologic adverse events and liver toxicity. A total of 25 RCTs involving 6,823 patients with CML and 6 types of TKIs were included. In terms of efficacy, second-generation TKIs such as dasatinib, nilotinib, and radotinib showed certain advantages in improving patients' MMR and CCyR compared to imatinib. Additionally, imatinib 800 mg provided better MMRs and CCyRs than imatinib 400 mg. As far as safety was concerned, there was no significant difference in the incidence of all grade adverse events among the different TKIs. All TKIs can cause serious grade 3-4 hematologic adverse events, including anemia, thrombocytopenia, and neutropenia. Dasatinib more likely caused anemia, bosutinib thrombocytopenia, and imatinib neutropenia, whereas nilotinib and flumatinib might have better safety profiles in terms of severe hematologic adverse events. For liver toxicity, radotinib 400 mg and imatinib 800 mg, respectively, had the highest likelihood of ranking first in incidence rates of all grade ALT and AST elevation. In CML, second-generation TKIs are more clinically effective than imatinib even if this last drug has a relatively better safety profile. Thus, as each second-generation TKI has a distinct clinical efficacy and safety, and is associated with different economic factors, its choice should be dictated by the specific patient clinical conditions (patient's specific disease characteristics, comorbid conditions, potential drug interactions, as well as their adherence). Nevertheless, due to the limited number of original research, additional high-quality studies are needed to achieve any firm conclusion on which second-generation TKI is the best choice for that peculiar patient.

A novel experimental model of MetALD in male mice recapitulates key features of severe alcohol-associated hepatitis.

The recent increase in the incidence of alcohol-associated hepatitis (AH) coincides with the obesity epidemic in the United States. However, current mouse models do not fully replicate the combined insults of obesity, metabolic dysfunction-associated steatohepatitis, and alcohol. The aim of this study was to develop a new mouse model that recapitulates the robust inflammatory and fibrotic phenotype characteristic of human MetALD. Eight- to 10-week-old male C57BL/6 mice were fed chow or high fat-cholesterol-sugar diet (metabolic dysfunction-associated steatohepatitis diet) and in each group, some received alcohol in drinking water (ad libitum) and weekly alcohol binges (EtOH) for 3 months. The liver was assessed for features of AH. MetALD mice displayed increased liver damage indicated by highly elevated ALT and bilirubin levels compared to all other groups. Liver steatosis was significantly greater in the MetALD mice compared to all other experimental groups. The inflammatory phenotype of MetALD was also recapitulated, including increased IL-6 and IL-1β protein levels as well as increased CD68+ macrophages and Ly6G+ neutrophils in the liver. Sirius red staining and expression of collagen 1, alpha-smooth muscle actin indicated advanced fibrosis in the livers of MetALD mice. In addition, indicators of epithelial-to-mesenchymal transition markers were increased in MetALD mice compared to all other groups. Furthermore, we found increased ductular reaction, dysregulated hedgehog signaling, and decreased liver synthetic functions, consistent with severe AH. Alcohol administration in mice combined with metabolic dysfunction-associated steatohepatitis diet recapitulates key characteristics of human AH including liver damage, steatosis, robust systemic inflammation, and liver immune cell infiltration. This model results in advanced liver fibrosis, ductular reaction, decreased synthetic function, and hepatocyte dedifferentiation, suggesting a robust model of MetALD in mice.

Association of Breastfeeding with Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis in mothers: A cross sectional survey

Objective: To determine the association of Breastfeeding with Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis in mothers.Methodology: A cross sectional study on randomly selected 280 mothers presented in the outpatient department of Sheikh Zayed Hospital, Rahim Yar Khan for different medical reasons from July to Dec 2023. Data collection commenced after taking ethical approval from the Institutional Review Board of the institute and taking informed verbal consent from study subjects. These mothers were divided into 2 groups. Group 1 which never breastfed their children and group 2 which breastfed their children for more than 6 months. Each group had 140 participants. Subject having history of alcohol consumption or used medicines like glucocorticoids, amiodarone, tamoxifen, and methotrexate were excluded from the study. Biodata of all the participants along with demographic profiles were obtained, who then went through an LFT and Lipid profile blood sampling and an USG abdomen. Results were recorded on a predesigned proforma. Serum ALT, AST, Serum bilirubin, serum LDL, HDL, Triglycerides, and Serum Cholesterol were determined by enzymatic assay and high-performance liquid chromatography methods. Data was analysed using SPSS v.26. Descriptive statistics was used to summarize the data. Mean and standard deviations were reported for continuous variables. Chi square test was used to compare the qualitative variables, with p value of less than 0.05 taken as significant.Results: Mean age ± SD of participants was 40±4 years, with group-1 having mean age of 38.1±5 years and group-2 having 40.4±3 years (p=0.4). The findings showed that frequency of NASH in patients who have not breastfed their children was higher 19 out of 140(13.6%) whereas the mothers who breastfed their children only have 5% frequency of NASH i.e. 7 out of 140 (P value = 0.01). Out of 140 patients who did not breastfeed their children 56 (40.0%) developed NAFLD, contrary to 140 patients who breastfed their children only 20 (14.3%) (P value = 0.00) got NAFLD. Elevated ALT and AST levels are significant for NAFLD and NASH. Lipid profile is a major indicator of NAFL and NASH.Conclusion: The frequency of NAFLD and NASH is significantly low in mothers who breastfed their children. The frequency further decreases if the period of breastfeeding was greater.

Clinical Characteristics and Maternal and Neonatal Outcomes of Pregnant Women Positive, Negative, and Recovered With COVID-19 Pneumonia

Background: The pandemic of coronavirus disease 2019 (COVID-19) has caused serious concerns about its potential adverse effects on pregnancy. There are limited data on maternal and neonatal outcomes of pregnant Hispanic women with COVID-19. Methods: This study was a retrospective chart review. This cohort included pregnant females between the ages of 18-60 who had tested positive for COVID-19 and tested negative for COVID-19 from the electronic medical records of Texas Tech Health Sciences Department of OB/GYN clinics, University Medical Center (UMC), and El Paso Children’s Hospital (EPCH) from March 2020 to June 2021, in addition to their neonates. Records were analyzed to collect information on demographics, BMI, gestational age, COVID status at the time of delivery, history of exposure to COVID, signs and symptoms of COVID, presenting symptoms, comorbidities, and treatment of COVID before and after delivery. Further, mode of delivery, pregnancy complications, complications during labor, and adverse outcomes (maternal death, admission to ICU, length of stay in ICU). We also collected diagnostic data. The control group included age-matched pregnant individuals without a diagnosis of COVID. The control group was evaluated for the same variables and outcome assessment. For the neonatal outcomes, the mothers were matched to the neonate. Data collected on neonatal outcomes included demographics, date of delivery, APGAR score, admission to the newborn nursery or NICU, the reason for NICU admission, birthweight, length, head circumference, fetal abnormalities, prematurity, neonatal death, COVID test results, breastfeeding (expressed or direct), and length of hospital stay. We also collected diagnostic data for neonates. Statistical analyses was performed using descriptive statistics for the various variables, a t-test to determine differences between the two groups for the continuous variables, and a chi-square test for the categorical variables. Results: During the period March 21, 2020 - June 15, 2021, 370 pregnant women, out of which 100 women were COVID-positive, 71 women who were recovered, and 188 controls. COVID-positive women had more elevated fibrinogen, WBC, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase but nonsignificant CRP levels. Most of the COVID-positive and COVID recovered women had preeclampsia during pregnancy, 29.24% COVID positive women delivered via C-section, while 68.42% of women delivered vaginally. The mean length of stay was 2.97 days for both groups. There 79.41% of women chose to breastfeed. One maternal death was recorded, while only two women had ICU admissions. Compared to the COVID-positive, the recovered women still had significantly elevated fibrinogen but not ALP, ALT, AST, and CRP. The COVID recovered women had lower counts of vaginal delivery (56.3%) and higher C-section rates (39.4%) among the three groups. The recovered group had higher premature deliveries (18%) than the other two groups (8%, 17%). Among the neonatal outcomes, there were four neonatal deaths in the COVID group, two neonates had COVID transmission during delivery, and 19.4 % of neonates were admitted to the NICU. Among neonatal vitals, blood pressure was higher in the positive (41%) and recovered (32.39%) groups than in controls (27.6%). Neonatal hypoglycemia was also higher in the recovered group (27.5%) than in the positive (17.11%) and control group (18.4%). Conclusions: Severe maternal and neonatal complications were not observed in pregnant women with COVID-19 pneumonia who had a vaginal or cesarean delivery. There were complications observed in women who recovered from COVID during pregnancy.

Assessing the Impact of Pomegranate Juice on Liver Tissue in Male Rats Exposed to a Commercial Energy Drink

The current study was designed to investigate the effect of pomegranate juice on some biochemical and histological variables resulting from dosing male rats with the energy drink Red Bull. In this study, 28 white male rats were used, divided into four groups, each involving seven animals, according to the following: G1 was given a physiological solution (5 ml/kg) and a standard diet for 120 days; G2 was given a dose of the energy drink Red Bull (volume 1 ml per 100 g); G3 was given pomegranate juice (5 ml/kg) first; then Red Bull; and G4 was given Red Bull first; and after six weeks, he was given pomegranate juice. The results showed that Red Bull consumption significantly elevated RBS, AST, ALT, TC, and TG levels. Pomegranate juice has the ability to reduce the concentration of RBS, AST, ALT, TC, and TG. Histological changes in the liver of animals that were given the Red Bull energy drink were represented by congestion of the central vein, degeneration, and necrosis of liver cells, with severe infiltration of inflammatory cells and a thick wall of the central vein (TW), as well as amyloid (AM) deposition, compared to the negative control group. The results of the histological examination showed that pomegranate juice could repair cellular tissue in the liver and make it similar to the tissue of a control normal group, denoting the possibility of using it in the diet and in treating atherosclerosis and heart disease. Keywords: Pomegranate juice, liver, rats, energy drink, rat model, atherosclerosis, heart disease.

Effect of hydroxy-α-sanshool on lipid metabolism in liver and hepatocytes based on AMPK signaling pathway

BackgroundWith the increasing awareness of the safety of traditional Chinese medicine and food, as well as in-depth studies on the pharmacological activity and toxicity of Zanthoxylum armatum DC. (ZADC), it has been found that ZADC is hepatotoxic. However, the toxic substance basis and mechanism of action have not been fully elucidated. Hydroxy-α-sanshool (HAS) belongs to an amide compound in the fruits of ZADC, which may be hepatotoxic. However, the specific effects of HAS, including liver toxicity, are unclear. PurposeThe objectives of this research was to determine how HAS affects hepatic lipid metabolism, identify the mechanism underlying the accumulation of liver lipids by HAS, and offer assurances on the safe administration of HAS. MethodsAn in vivo experiment was performed by gavaging C57 BL/6 J mice with various dosages of HAS (5, 10, and 20 mg/kg). Biochemical indexes were measured, and histological analysis was performed to evaluate HAS hepatotoxicity. Hepatic lipid levels were determined using lipid indices and oil red O (ORO) staining. Intracellular lipid content were determined by biochemical analyses and ORO staining after treating HepG2 cells with different concentrations of HAS in vitro. Mitochondrial membrane potential, respiratory chain complex enzymes, and ATP levels were assessed by fluorescence labeling of mitochondria. The levels of proteins involved in lipogenesis and catabolism were determined using Western blotting. ResultsMice in the HAS group had elevated alanine and aspartate aminotransferase blood levels as well as increased liver index compared with the controls. The pathological findings showed hepatocellular necrosis. Serum and liver levels of triglycerides, total cholesterol, and low-density lipoprotein cholesterol levels were increased, whereas high-density lipoprotein cholesterol levels decreased. The ORO staining findings demonstrated elevated liver lipid levels. In vitro experiments demonstrated a notable elevation in triglyceride and total cholesterol levels in the HAS group. ATP, respiratory chain complex enzyme gene expression, mitochondrial membrane potential, and mitochondrial number were reduced in the HAS group. The levels of lipid synthesis-associated proteins (ACC, FASN, and SREBP-1c) were increased, and lipid catabolism-associated protein levels (PPARα and CPT1) and the p-AMPK/AMPK ratio were decreased in vivo and in vitro. ConclusionHAS has hepatotoxic effects, which can induce fatty acid synthesis and mitochondrial function damage by inhibiting the AMPK signaling pathway, resulting in aberrant lipid increases.

Utility of Radiological Follow Up of Main-Duct Intraductal Papillary Mucinous Neoplasms and Mixed-Type Intraductal Papillary Mucinous Neoplasms.

Intraductal papillary mucinous neoplasms (IPMNs) have the potential to evolve into pancreatic adenocarcinoma (PDAC). While main-duct IPMNs (MD-IPMNs), involving the main pancreatic duct (MPD), are less common than side-branch IPMNs (SB-IPMNs) or mixed-type IPMNs (mixed-IPMNs), their malignant transformation potential is far greater. Controversy exists between different guidelines in terms of recommended management strategies. This study was aimed at assessing the utility of the radiological follow up of MD-IPMNs and mixed-type IPMNs, including prevalence of worrisome radiological findings as well as clinical and laboratory parameters, and their correlation with the development of progression or pancreatic adenocarcinoma. Eighty-four patients with MD-IPMNs or mixed-type IPMNs who underwent at least one magnetic resonance cholangiopancreatography (MRCP) were included. Clinical and laboratory data were obtained retrospectively. A cross-sectional analysis was carried out to establish clinical and laboratory parameters associated with development of PDAC. A retrospective cohort analysis was performed on 44 patients who had at least six months of follow up, trying to identify factors correlating with worrisome radiological features. Nine cases (10.7%) of PDAC were recorded in this cohort. The laboratory and imaging factors associated with cyst size progression greater than 5 mm during follow up were elevated alanine transaminase (ALT) levels, the maximal cyst size, and the MPD diameter. Cross-sectional analysis indicated that PDAC was associated with nausea (p = 0.01), as well as increased levels of aspartate aminotransferase (AST) (p = 0.05), gamma glutamyl transpeptidase (GGT) (p = 0.01), and alkaline phosphatase (ALP) (p = 0.01). Elevated levels of liver enzymes were associated with IPMN progression and, subsequently, the development of PDAC. ALT levels, maximal cyst size, and MPD diameter are associated with the progression of cyst size. These data may aid in risk-stratifying patients when determining the follow up approach for IPMNs.

Metabolic Comorbidities in Pediatric Psoriasis-A Comparative Cross-Sectional Study in South-Asian Children.

There is only limited data on the association between psoriasis and metabolic comorbidities in South-Asian children. To examine metabolic comorbidities among South-Asian children with and without psoriasis. A hospital-based, comparative, cross-sectional study was conducted in children with and without psoriasis over 19 months. Anthropometric, clinical, and metabolic comorbidity details (including disease extent and severity scores, obesity, systemic hypertension, diabetes mellitus, lipid abnormalities, and metabolic syndrome) were obtained in both groups according to standard criteria. Fifty-eight children with psoriasis (25 males/33 females, age 11.3 ± 3.0 years, range 4 to 17 years) and 62 children without psoriasis (37 males/25 females, age 11.0 ± 3.6 years, range 4 to 18 years) were recruited. The prevalence of obesity (31.0% versus 14.5%, P = 0.031, odds ratio 2.65) and metabolic syndrome (18.6% versus 4.6%, P = 0.044, odds ratio 4.68) were higher in children with psoriasis than without. The prevalence of other metabolic comorbidities (systemic hypertension, pre-diabetes, lipid abnormalities, elevated serum alanine aminotransferase, and non-alcoholic fatty liver disease) was not different between children with and without psoriasis and between obese and non-obese children with psoriasis. Among children with psoriasis, those with abdominal obesity had significantly lower disease severity and extent scores than those without. Psoriasis is associated with a significantly higher prevalence of obesity and close to significantly higher prevalence of metabolic syndrome in South-Asian children. Screening for metabolic comorbidities is essential even in non-obese children with psoriasis. Disease extent and severity are less in obese compared to non-obese South-Asian children with psoriasis.

Peripherally Restricted CB1 Receptor Inverse Agonist JD5037 Treatment Exacerbates Liver Injury in MDR2-Deficient Mice.

Previous research highlighted the involvement of the cannabinoid CB1 receptor in regulating the physiology of hepatocytes and hepatic stellate cells. The inhibition of the CB1 receptor via peripherally restricted CB1 receptor inverse agonist JD5037 has shown promise in inhibiting liver fibrosis in mice treated with CCl4. However, its efficacy in phospholipid transporter-deficiency-induced liver fibrosis remains uncertain. In this study, we investigated the effectiveness of JD5037 in Mdr2-/- mice. Mdr2 (Abcb4) is a mouse ortholog of the human MDR3 (ABCB4) gene encoding for the canalicular phospholipid transporter. Genetic disruption of the Mdr2 gene in mice causes a complete absence of phosphatidylcholine from bile, leading to liver injury and fibrosis. Mdr2-/- mice develop spontaneous fibrosis during growth. JD5037 was orally administered to the mice for four weeks starting at eight weeks of age. Liver fibrosis, bile acid levels, inflammation, and injury were assessed. Additionally, JD5037 was administered to three-week-old mice to evaluate its preventive effects on fibrosis development. Our findings corroborate previous observations regarding global CB1 receptor inverse agonists. Four weeks of JD5037 treatment in eight-week-old Mdr2-/- mice with established fibrosis led to reduced body weight gains. However, contrary to expectations, JD5037 significantly exacerbated liver injury, evidenced by elevated serum ALT and ALP levels and exacerbated liver histology. Notably, JD5037-treated Mdr2-/- mice exhibited significantly heightened serum bile acid levels. Furthermore, JD5037 treatment intensified liver fibrosis, increased fibrogenic gene expression, stimulated ductular reaction, and upregulated hepatic proinflammatory cytokines. Importantly, JD5037 failed to prevent liver fibrosis formation in three-week-old Mdr2-/- mice. In summary, our study reveals the exacerbating effect of JD5037 on liver fibrosis in genetically MDR2-deficient mice. These findings underscore the need for caution in the use of peripherally restricted CB1R inverse agonists for liver fibrosis treatment, particularly in cases of dysfunctional hepatic phospholipid transporter.

Clinical performance of ultrasonic backscatter parametric and nonparametric statistics in detecting early hepatic steatosis

Diagnosis of early hepatic steatosis would allow timely intervention. B-mode ultrasound imaging was in question for detecting early steatosis, especially with a variety of concomitant parenchymal disease. This study aimed to use the surgical specimen as a reference standard to elucidate the clinical performance of ultrasonic echogenicity and backscatter parametric and nonparametric statistics in real-world scenarios. Ultrasound radio-frequency (RF) signals of right liver lobe and patient data were collected preoperatively. Surgical specimen was then used to histologically determine staging of steatosis. A backscatter nonparametric statistic (h), a known backscatter parametric statistic, i.e., the Nakagami parameter (m), and a quantitative echo intensity (env) were calculated. Among the 236 patients included in the study, 93 were grade 0 (<5% fat) and 143 were with steatosis. All the env, m and h statistics had shown significant discriminatory power of steatosis grades (AUC = 0.643–0.907 with p-value < 0.001). Mann-Whitney U tests, however, revealed that only the backscatter statistics m and h were significantly different between the groups of grades 0 and 1 steatosis. The two-way ANOVA showed a significant confounding effect of the elevated ALT on env (p-value = 0.028), but no effect on m or h. Additionally, the severe fibrosis was found to be a significant covariate for m and h. Ultrasonic signals acquired from different scanners were found linearly comparable.

Reasonability of Frequent Laboratory Analyses during Therapy with Nivolumab and Nivolumab+Ipilimumab in Patients with Advanced or Metastatic Renal Cell Carcinoma during the Phase 2 Clinical Trial TITAN-RCC.

In clinical trials, laboratory values are assessed with high frequency. This can be stressful for patients, resource intensive, and difficult to implement, for example in office-based settings. In the prospective, multicentre phase 2 TITAN-RCC trial (NCT02917772), we investigated how many relevant changes in laboratory values would have been missed if laboratory values had been assessed less frequently. Patients with metastatic renal cell carcinoma (n = 207) received a response-based approach with nivolumab and nivolumab+ipilimumab boosts for non-response. We simulated that laboratory values were obtained before every second dose instead of every dose of the study drug(s). We assessed elevated leukocyte counts, alanine aminotransferase, aspartate aminotransferase, bilirubin, creatinine, amylase, lipase, and thyroid-stimulating hormone. Dose delay and discontinuation criteria were defined according to the study protocol. With the reduced frequency of laboratory analyses, dose delay criteria were rarely missed: in a maximum of <0.1% (3/4382) of assessments (1% [2/207] of patients) during nivolumab monotherapy and in a maximum of 0.2% (1/465) of assessments (1% [1/132] of patients) during nivolumab+ipilimumab boosts. An exception was lipase-related dose delay which would have been missed in 0.6% (25/4204) of assessments (7% [15/207] of patients) during nivolumab monotherapy and in 0.8% (4/480) of assessments (3% [4/134] of patients) during nivolumab+ipilimumab boosts, but would have required the presence of symptoms. Discontinuation criteria would have only been missed for amylase (<0.1% [1/3965] of assessments [0.5% (1/207) of patients] during nivolumab monotherapy, none during nivolumab+ipilimumab boosts) and lipase (0.1% [5/4204] of assessments [2% (4/207) of patients] during nivolumab monotherapy; 0.2% [1/480] of assessments [0.7% (1/134) of patients] during nivolumab+ipilimumab boosts). However, only symptomatic patients would have had to discontinue treatment due to amylase or lipase laboratory values. In conclusion, a reduced frequency of laboratory testing appears to be acceptable in asymptomatic patients with metastatic renal cell carcinoma treated with nivolumab or nivolumab+ipilimumab.

Analysis of serum ascites albumin gradient (SAAG) in cats with hepatic disorder

Three Persian breed cats were diagnosed to be having hepatitis. Clinical examination revealed dullness, dehydration, poor body condition and fluid thrill on the abdominal palpation. Radiography and ultrasonography revealed ground glass appearance of the abdomen and anechoic fluid in the abdomen respectively. Elevated serum ascites albumin gradient with elevated serum alanine transaminase levels were noticed in these cats

Investigating the tamoxifen/high-fat diet synergy: a promising paradigm for nonalcoholic steatohepatitis induction in a rat model

Non-alcoholic steatohepatitis (NASH) is a severe liver condition characterized by excessive fat deposition, ballooning, and lobular inflammation. This investigation was conducted to estimate the capability of concomitant tamoxifen administration (TAM) with a high fat diet (HFD) to induce a reliable NASH model that mimics human NASH features. Rats were administered TAM (25 mg/kg/day p.o.) and consumed HFD for 5 weeks. A time-course investigation was conducted to determine the optimal time for NASH development. Liver function indices, hepatic lipid profile factors, oxidative stress biomarkers, and inflammatory mediators were estimated. Additionally, macroscopic and microscopic changes were examined. Compared with the time-matched control group receiving vehicle alone, TAM/HFD significantly impaired liver function indices represented as marked elevation in ALT, AST, and ALP serum levels. TAM/HFD significantly increased lipid profile factors including high TG and TC hepatic levels. Additionally, TAM/HFD remarkably raised hepatic levels of TNF-α and IL-17 and significantly decreased IL-10. The combination also increases the oxidative status evidenced by high content of MDA as well as low activity of GPx and SOD. Accordingly, the combination of TAM and HFD for 5 weeks collaboratively promotes NASH development by initiating compromised hepatocyte functionality, elevated lipid levels, oxidative stress, and liver inflammation.Graphical abstract

Effectiveness and predictors of weight loss response to phentermine plus lifestyle modifications among youth in a paediatric weight management clinical setting.

Anti-obesity medications (AOMs) are promising lifestyle modification (LSM) adjuncts for obesity treatment, and phentermine is commonly prescribed in paediatric weight management clinics. Determining 'real-world' AOM effectiveness and characteristics predicting response is important. We sought to describe phentermine plus LSM effectiveness and identify baseline characteristics predicting response. This was a retrospective cohort study among youth seen in a US academic-based weight management clinic from 2012 to 2020. Baseline characteristics (e.g., body mass index (BMI), liver transaminases, eating-related behaviours) and outcomes (%BMI of 95th percentile (%BMIp95), BMI, %BMI change, weight) were determined through electronic health records and intake surveys. Among 91 youth prescribed phentermine plus LSM over 8 years (mean %BMIp95 150%), %BMIp95 was statistically significantly reduced at 1.5, 3, 6 and 12 months (peak reduction 10.9 percentage points at 6 months; p < 0.001). Considering multiple comparisons, the presence of baseline elevated alanine aminotransferase was associated with statistically significant smaller 1.5-month %BMIp95 reductions (p = 0.001) and higher food responsiveness with smaller 3- (p = 0.001) and 6-month (p < 0.001) reductions. Phentermine plus LSM reduced %BMIp95 among youth in a weight management clinic, and baseline characteristics may help determine those more or less likely to respond. Prospective studies are needed to further characterize effectiveness and confirm response predictors.

Early Detection of Intrahepatic Cholestasis of Pregnancy: Correlation Between Liver Enzymes and Adverse Fetal Outcomes

Background: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that occurs in late pregnancy and leads to elevated bile acid levels in the maternal serum, posing risks to fetal health, including preterm labor and fetal distress. Understanding the relationships between liver enzyme levels and fetal outcomes can guide early diagnostic and management strategies. Objective: To evaluate the significance of early detection of ICP through routine liver enzyme tests (AST and ALT) and its correlation with adverse fetal outcomes to inform clinical practices in regions with limited access to advanced diagnostic tools. Methods: This cross-sectional study was conducted at the Ittefaq Hospital Trust, Lahore, involving 90 pregnant women categorized into three groups based on gestational age and ICP symptoms. Group A consisted of 30 women at 30-34 weeks of gestation, Group B included 30 women at 34-37 weeks, and Group C comprised 30 healthy pregnant women as controls. Serum AST and ALT levels were measured at day 0, 30, and 45. Fetal outcomes were monitored through ultrasound and medical records. Statistical analysis was performed using SPSS version 25, employing descriptive statistics and ANOVA to compare enzyme levels and fetal outcomes across groups. Results: Group 2 exhibited significantly higher mean AST levels (96.58 U/L) and ALT levels (183.10 U/L) compared to Group 1 (AST: 49.95 U/L, ALT: 100.90 U/L) and Group 3 (AST: 25.30 U/L, ALT: 35.05 U/L). Adverse fetal outcomes, including intrauterine growth restriction (IUGR), were notably higher in Group 2 (76.7%) compared to Group 1 (13.33%) and Group 3 (0%). The statistical significance was marked with a p-value &lt; 0.05 across all comparisons. Conclusion: Elevated liver enzymes, specifically AST and ALT, are strongly associated with adverse fetal outcomes in ICP. Early detection and monitoring of these enzymes can be crucial in preventing fetal complications, particularly in resource-limited settings where traditional diagnostic measures are inaccessible.

Prediction of the liver safety profile of a first-in-class myeloperoxidase inhibitor using quantitative systems toxicology modeling

The novel myeloperoxidase inhibitor verdiperstat was developed as a treatment for neuroinflammatory and neurodegenerative diseases. During development, a computational prediction of verdiperstat liver safety was performed using DILIsym v8A, a quantitative systems toxicology (QST) model of liver safety. A physiologically-based pharmacokinetic (PBPK) model of verdiperstat was constructed in GastroPlus 9.8, and outputs for liver and plasma time courses of verdiperstat were input into DILIsym. In vitro experiments measured the likelihood that verdiperstat would inhibit mitochondrial function, inhibit bile acid transporters, and generate reactive oxygen species (ROS); these results were used as inputs into DILIsym, with two alternate sets of parameters used in order to fully explore the sensitivity of model predictions. Verdiperstat dosing protocols up to 600 mg BID were simulated for up to 48 weeks using a simulated population (SimPops) in DILIsym. Verdiperstat was predicted to be safe, with only very rare, mild liver enzyme increases as a potential possibility in highly sensitive individuals. Subsequent Phase 3 clinical trials found that ALT elevations in the verdiperstat treatment group were generally similar to those in the placebo group. This validates the DILIsym simulation results and demonstrates the power of QST modelling to predict the liver safety profile of novel therapeutics.

Factors Affecting Health-related Quality of Life in Patients with Chronic Viral Hepatitis in Kazakhstan

Abstract Background: Chronic viral hepatitis is one of the main causes leading to lower health-related quality of life (HRQoL) in patients, so its performance is significantly worse than that of patients with other liver diseases. It is common for a significant percentage of patients infected with hepatitis viruses to have low scores that are independent of the degree of disease activity and in the absence of disease progression. There are many studies evaluating HRQoL in patients with chronic viral hepatitis, but studies examining predictors of reduced quality of life in patients are still scarce. Aim: This study aimed to assess factors affecting HRQoL in patients with chronic viral hepatitis in Kazakhstan. Methods: A cross-sectional study was conducted with the participation of 233 patients with chronic viral hepatitis at the Infectious Diseases Hospital of the Shymkent city and the Hepatological Center of the Shymkent Regional Clinical Hospital for the period from September 2020 to March 2022. The EuroQol-five dimensional questionnaire (EQ-5D) and the EuroQol-visual analogue scale EQ-VAS were used to assess the quality of life. Results: A total of 233 patients diagnosed with chronic viral hepatitis were enrolled in the study. The average value of the EQ-5D index scores in the total number of patients with chronic viral hepatitis was low and amounted to 0.63 ± 0.3. The indicator of the visual analog scale EQ-VAS in the total number of patients was 73.1 ± 15.3. Multiple regression analysis also showed that age (P &lt; 0.001), female (P &lt; 0.014), the stage of liver fibrosis (P &lt; 0.008), alanine transaminase (ALT) level (P &lt; 0.027), and high viral load (P &lt; 0.006) were variables significantly correlating with HRQoL in patients with chronic viral hepatitis. Conclusions: The quality of life in patients with chronic viral hepatitis in this study was low. The main factors leading to a decrease in the quality of life are older age, belonging to the female sex, advanced stage of liver fibrosis, elevated ALT levels, and high viral load. Strengthening social and medical support for patients with chronic viral hepatitis, in particular, with a late stage of the disease, can contribute to improving the quality of life in this category of patients, but further research is needed.

Elevated serum hepatic transaminases in apical periodontitis individuals.

Apical periodontitis (AP) is the chronic inflammation of the periradicular tissues in response to root canal infection. Whilst AP has been linked with systemic inflammation and noncommunicable diseases, its potential association with nonalcoholic fatty liver disease (NAFLD) is unknown. We aimed to evaluate the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels as surrogate markers of hepatic injury, and the systemic inflammatory burden in otherwise healthy individuals with and without AP diagnosis. Cross-sectional study. Individuals with AP (n = 30) and healthy controls (n = 29) were recruited. The number, mean diameter (mm) and periapical index of the apical lesions of endodontic origin (ALEO) were assessed. ALT and AST levels (pg/mL) were measured through enzyme-linked immunosorbent assays. The serum levels of TNF-α, IL-4, IL-9, IL-10, IL-17A and IL-22 were evaluated by Multiplex assay. Inferential analysis was performed using t-test or Mann-Whitney tests according to data distribution and linear regression models. Data were analysed with StataV16 (p < .05). ALT and AST levels were significantly higher in individuals with AP compared to controls (p < .05). Serum inflammatory biomarkers showed no significant differences between the study groups. Bivariate and multivariate analyses confirmed that AP diagnosis was independently associated with ALT and AST elevations (p < .05). Additionally, the number of ALEO positively influenced AST levels (p = .002). IL-22 on the other hand, was associated with reduced ALT levels (p = .043). AP is associated with higher serum hepatic transaminases ALT and AST, potentially contributing to NAFLD physiopathology in young adults.