Changes In Liver Enzymes Research Articles

Liver injury in cynomolgus monkeys following intravenous and intrathecal scAAV9 gene therapy delivery

Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 administration varies from asymptomatic transaminase elevation with minimal to mild microscopic changes to symptomatic elevations of liver function and thromboinflammatory markers with microscopic changes consistent with marked hepatocellular necrosis and deteriorating clinical condition. These transient acute liver injury marker elevations occur from 3-4days post intravenous administration to ∼2weeks post intrathecal administration. No transaminase elevation or microscopic changes were observed with intrathecal administration of empty capsids or a "promoterless genome" vector, suggesting that liver injury after cerebrospinal fluid dosing in nonhuman primates is driven by viral transduction and transgene expression. Co-administration of prednisolone after intravenous or intrathecal dosing did not prevent liver enzyme or microscopic changes despite a reduction of T lymphocyte infiltration in liver tissue. Similarly, co-administration ofrituximab/everolimus with intrathecal dosing failed to blockAAV-driven hepatotoxicity. Self-complementary AAV-inducedacute liver injury appears to correlate with high hepatocellular vector load, macrophage activation, and type 1 interferon innate virus-sensing pathway responses. The current work characterizes key aspects pertaining to early AAV-driven hepatotoxicity in cynomolgus macaques, highlighting the usefulness of this nonclinical species in that context.

HEPATOPROTECTIVE EFFECT OF SEA BUCKTHORN BERRY SEED OIL IN CYCLOPHOSPHAMIDE-INDUCED HEPATIC TOXICITY IN BALB/c MICE

Background: Chemotherapy-induced hepatotoxicity can be mitigated by use of antioxidants, which may help the liver to recover its endogenous antioxidant mechanism. The objective of this study was to determine the effectiveness of sea buckthorn berry seed oil (SBO) in attenuating cyclophosphamide-induced changes in liver enzymes and liver histology in BALB/c mice. Methods: This experimental study was conducted in Physiology Department of Foundation University School of Health Sciences (FUSH), in collaboration with Pathology Department, FUSH and National Institute of Health, Islamabad from Jan 2018 to Jun 2019. Thirty healthy male BALB/c mice were divided into 3 groups of 10 each. Group-1 served as control. Group-2 received cyclophosphamide (25 mg/Kg body weight) intraperitoneally for 10 days. Group-3 was co-administered cyclophosphamide (same dose) with of sea buckthorn berry seed oil (40 mg/Kg body weight) orally for ten days. All animals were sacrificed on 11th day. Serum levels of liver enzymes as liver injury biomarkers were assayed. Liver histopathology was carried out for evidence of hepatic injury and recovery. Results: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) increased significantly in Group-2 (p<0.05). In Group-3, the rise in hepatic injury serum markers was significantly less than Group-2 (p<0.05). Upon histological examination, Group-2 was grade 5 according to Kleiner’s scoring system for steatohepatitis, and had grade 2 sinusoidal dilatation on Rubbia-Brandt grading system. These changes were significantly less in Group-3 (p<0.05). Conclusion: Co-administration of SBO mitigated the CP-induced rise in hepatic injury biomarkers and sinusoidal injury. Pak J Physiol 2023;19(2):20–4

369-OR: Continued Weight Loss with Semaglutide Once-Weekly in Patients without Type 2 Diabetes and Postbariatric Treatment Failure

Purpose: Recently, we published promising retrospective 6-months follow-up data on the effectiveness of semaglutide 0.5mg once-weekly in patients with weight regain (WR) or insufficient weight loss (IWL) following bariatric metabolic surgery (BS). Therefore, we aimed to investigate whether weight loss was sustained over a 12-months period with semaglutide in patients without type 2 diabetes (T2D) with WR or IWL. Materials and Methods: Postbariatric patients without T2D with WR or IWL (n=29) were included in the analysis. The primary endpoint was weight loss 12 months after initiation of adjunct treatment. Secondary endpoints included change in BMI, HbA1c, lipid profile, hs-CRP and liver enzymes. Results: Total weight loss during semaglutide treatment added up to 14.7±8.9% (mean±SD, p<0.001) after 12 months. Categorical weight loss was >5% in 89.7% of patients, >10% in 62.1% of patients, >15% in 34.5% of patients, >20% in 24.1% of patients and >25% in 17.2% of patients. Among patients with prediabetes at baseline (n=6), 12-months treatment led to normoglycemia in all patients (p<0.05). Conclusion: Treatment options to manage postbariatric treatment failure are scarce, weight loss medications are not approved for use in the postbariatric patient population. Our results imply a clear benefit of adjunct treatment with semaglutide in postbariatric patients. Disclosure A.Lautenbach: Other Relationship; Novo Nordisk, Lilly. J.Wagner: None. F.D.Stoll: None. J.Aberle: Advisory Panel; Novo Nordisk, Speaker's Bureau; Novo Nordisk.

A comparative multi-level toxicity assessment of carbon-based Gd-free dots and Gd-doped nanohybrids from coffee waste: hematology, biochemistry, histopathology and neurobiology study

Here, a comparative toxicity assessment of precursor carbon dots from coffee waste (cofCDs) obtained using green chemistry principles and Gd-doped nanohybrids (cofNHs) was performed using hematological, biochemical, histopathological assays in vivo (CD1 mice, intraperitoneal administration, 14 days), and neurochemical approach in vitro (rat cortex nerve terminals, synaptosomes). Serum biochemistry data revealed similar changes in cofCDs and cofNHs-treated groups, i.e. no changes in liver enzymes' activities and creatinine, but decreased urea and total protein values. Hematology data demonstrated increased lymphocytes and concomitantly decreased granulocytes in both groups, which could evidence inflammatory processes in the organism and was confirmed by liver histopathology; decreased red blood cell-associated parameters and platelet count, and increased mean platelet volume, which might indicate concerns with platelet maturation and was confirmed by spleen histopathology. So, relative safety of both cofCDs and cofNHs for kidney, liver and spleen was shown, whereas there were concerns about platelet maturation and erythropoiesis. In acute neurotoxicity study, cofCDs and cofNHs (0.01 mg/ml) did not affect the extracellular level of L-[14C]glutamate and [3H]GABA in nerve terminal preparations. Therefore, cofNHs demonstrated minimal changes in serum biochemistry and hematology assays, had no acute neurotoxicity signs, and can be considered as perspective biocompatible non-toxic theragnostic agent.

Hepatic fibrosis: a manifestation of the liver disease evolution in patients with Ataxia-telangiectasia

BackgroundAtaxia-telangiectasia (A-T) is a DNA repair disorder characterized by changes in several organs and systems. Advances in clinical protocols have resulted in increased survival of A-T patients, however disease progression is evident, mainly through metabolic and liver changes.ObjectiveTo identify the frequency of significant hepatic fibrosis in A-T patients and to verify the association with metabolic alterations and degree of ataxia.MethodsThis is a cross-sectional study that included 25 A-T patients aged 5 to 31 years. Anthropometric data, liver, inflammatory, lipid metabolism and glucose biomarkers (oral glucose tolerance test with insulin curve—OGTT) were collected. The Cooperative Ataxia Rating Scale was applied to assess the degree of ataxia. The following were calculated: Homeostasis Model Assessment—Insulin Resistance, Homeostasis Model Assessment—Adiponectin (HOMA-AD), Matsuda index, aspartate aminotransferase (AST): platelet ratio index, nonalcoholic fatty liver disease fibrosis score and BARD score. Liver ultrasonography and transient liver elastography by FibroScan® were performed.ResultsSignificant hepatic fibrosis was observed in 5/25 (20%). Patients in the group with significant hepatic fibrosis were older (p < 0.001), had lower platelet count values (p = 0.027), serum albumin (p = 0.019), HDL-c (p = 0.013) and Matsuda index (p = 0.044); and high values of LDL-c (p = 0.049), AST (p = 0.001), alanine aminotransferase (p = 0.002), gamma-glutamyl transferase (p = 0.001), ferritin (p = 0.001), 120-min glycemia by OGTT (p = 0.049), HOMA-AD (p = 0.016) and degree of ataxia (p = 0.009).ConclusionsA non-invasive diagnosis of significant hepatic fibrosis was observed in 20% of A-T patients associated with changes in liver enzymes, ferritin, increased HOMA-AD, and the severity of ataxia in comparison with patients without hepatic fibrosis.

Efficient prime editing in mouse brain, liver and heart with dual AAVs

Realizing the promise of prime editing for the study and treatment of genetic disorders requires efficient methods for delivering prime editors (PEs) in vivo. Here we describe the identification of bottlenecks limiting adeno-associated virus (AAV)-mediated prime editing in vivo and the development of AAV-PE vectors with increased PE expression, prime editing guide RNA stability and modulation of DNA repair. The resulting dual-AAV systems, v1em and v3em PE-AAV, enable therapeutically relevant prime editing in mouse brain (up to 42% efficiency in cortex), liver (up to 46%) and heart (up to 11%). We apply these systems to install putative protective mutations in vivo for Alzheimer’s disease in astrocytes and for coronary artery disease in hepatocytes. In vivo prime editing with v3em PE-AAV caused no detectable off-target effects or significant changes in liver enzymes or histology. Optimized PE-AAV systems support the highest unenriched levels of in vivo prime editing reported to date, facilitating the study and potential treatment of diseases with a genetic component.

Thymus linearis Extracts Ameliorate Indices of Metabolic Syndrome in Sprague Dawley Rats.

The extract library (n-hexane (NH), ethyl acetate (EA), methanol (M), distilled water (DW), and combined extract (CE)) was standardized using in vitro phytochemical, antioxidant, and α-amylase inhibition assays, after which the protective effect of selected "hit," i.e., CE against metabolic syndrome, was determined in vivo, using rats fed a high-fat diet supplemented with additional cholesterol administration. CE was administered to Sprague Dawley rats in high dose as 100 mg/kg in carboxymethyl cellulose (CMC) (1 ml; 0.75% in DW) and low-dose group as 50 mg/kg in CMC (0.5 ml; 0.75% in DW). After 10 weeks, the effects of CE on insulin resistance, lipid metabolism, nonalcoholic fatty liver disease (NAFLD), oxidative stress, and genotoxicity were assessed through histological, biochemical, and hematological investigations. Phytochemical analysis including RP-HPLC analysis of the extracts showed that flavonoids and phenolics (myricetin, kaempferol, and apigenin), previously known to be effective against obesity and diabetes, are present in the extracts. Antioxidant studies revealed that the plant possesses a highly significant (p < 0.05) concentration of antioxidants. Satisfactory α-amylase inhibitory activity was also observed in in vitro experiments. In vivo studies showed that CE-administered animals had significantly (p < 0.05) lower weight gain and smaller adipocytes than the control group. Moreover, CE resisted any significant (p < 0.05) change in the organ weights. Analogous to findings from its traditional use, the plant extract had a positive modulatory effect on insulin resistance and hyperglycemia. The study also indicated that CE resisted high-fat diet-induced disturbance in lipid profile and countered any pathological changes in liver enzymes caused by fat-infused diet. Furthermore, a study on endogenous antioxidant levels indicated that CE was effective in maintaining catalase and peroxidase levels within the normal range and resisted the effects of lipid peroxidation of thiobarbituric acid reactive substances. In principle, the current study's findings scientifically validate the implication of T. linearis in metabolic syndrome and recommend further studies on molecular insights of the observed therapeutic activity.

Ursodeoxycholic Acid Use After Bariatric Surgery: Effects on Metabolic and Inflammatory Blood Markers

BackgroundIn addition to the reduction of symptomatic gallstone disease, ursodeoxycholic acid (UDCA) might also have beneficial metabolic effects after bariatric surgery. We examined the impact of UDCA on liver enzymes, hemoglobin A1c (HbA1c), lipids, and inflammation markers.MethodsPatients in the UPGRADE trial (placebo-controlled, double-blind) were randomized between UDCA 900 mg daily or placebo pills for 6 months after bariatric surgery. Patients without blood measurements pre- or 6 months postoperatively were excluded. The change in liver enzymes, Hba1c, lipids, and inflammation markers after surgery were compared between the UDCA and placebo group, followed by a postoperative cross-sectional comparison.ResultsIn total, 513 patients were included (age [mean ± SD] 45.6 ± 10.7 years; 79% female). Preoperative blood values did not differ between UDCA (n = 266) and placebo (n = 247) groups. Increase of alkaline phosphatase (ALP) was greater in the UDCA group (mean difference 3.81 U/l [95%CI 0.50 7.12]). Change in other liver enzymes, HbA1c, lipids, and CRP levels did not differ. Postoperative cross-sectional comparison in 316 adherent patients also revealed a higher total cholesterol (mean difference 0.25 mg/dl [95%CI 0.07–0.42]), lower aspartate aminotransferase (mean difference −3.12 U/l [−5.16 – −1.08]), and lower alanine aminotransferase level (mean difference −5.89 U/l [−9.41 – −2.37]) in the UDCA group.ConclusionUDCA treatment leads to a higher, but clinically irrelevant increase in ALP level in patients 6 months after bariatric surgery. No other changes in metabolic or inflammatory markers were observed. Except for the reduction of gallstone formation, UDCA has no effects after bariatric surgery.Graphical

Chronic Effects of Oral Cannabidiol Delivery on 24-h Ambulatory Blood Pressure in Patients with Hypertension (HYPER-H21-4): A Randomized, Placebo-Controlled, and Crossover Study.

Background: Recent data indicate that cannabidiol (CBD), a nonintoxicating constituent of cannabis, is involved in several aspects of cardiovascular regulation, including blood pressure (BP). However, the impact of chronic CBD administration on 24-h BP and vascular health has not been previously examined in patients with hypertension. The primary aim of this randomized, triple-blind, placebo-controlled, and crossover study was to examine the influence of chronic CBD on 24-h ambulatory BP and arterial stiffness in hypertensive patients. Methods: Seventy patients with mild or moderate primary hypertension, who were untreated or receiving standard of care therapy, were randomly assigned to receive either 5 weeks of oral CBD or placebo-matched controls. Following a >2-week washout period, patients were crossed over to alternate therapy. The primary outcome of the study was dynamic in 24-h ambulatory BP and was assessed using two-way repeated measure analysis of variance. Results: Administration of CBD reduced average 24 h mean, systolic, and diastolic BP after 2.5 weeks (-3.22±0.90 mmHg [95% confidence interval -1.01 to -5.44 mmHg], -4.76±1.24 mmHg [-1.72 to -7.80 mmHg], and -2.25±0.80 mmHg [-0.30 to -6.01 mmHg], respectively (all p<0.05); however, these values largely remained stable following the uptitration of CBD dosing. There were no changes in liver enzymes or serious adverse events (AEs). There was no significant difference in pulse wave velocity (group×factor interaction: F=1.50, p=0.226) at different time points, regardless of the intervention arm. Conclusions: In conclusion, chronic administration of CBD reduces ambulatory BP in those with untreated and treated hypertension. In addition, lack of serious AEs implies safety and tolerability of the above-noted CBD formulation. ClinicalTrials.gov ID: NCT05346562, Registered April 6th 2022.

Comparing mixed oil to soybean oil lipid emulsion in patients on home parenteral nutrition: a pilot prospective double-blind, crossover, randomized trial

BackgroundHome parenteral nutrition (HPN) can be associated with increased liver enzymes, catheter-related bloodstream infections (CRBSI), and hospitalizations. Mixed oil (MO) versus soybean oil (SO) lipid emulsion reduces risks in hospitalized patients, but there are no randomized double-blinded controlled trials in HPN. Therefore, the primary objective was to test the study’s feasibility such as recruitment and retention in the HPN population and the secondary objective was to assess changes in liver enzymes between MO and SO as well as other clinical and biochemical outcomes.MethodsThis 13-month prospective double-blind crossover randomized pilot trial took place in Toronto, Canada. Participants were HPN patients who were a part of the HPN program at Toronto General Hospital. We recruited patients from the HPN program. HPN patients receiving SO were randomized to either MO or SO, and the study duration was 6 months in each arm (MO or SO) with a 1-month washout period resuming SO. As this is a crossover trial design, the patient is his/her own control. The main outcome measures were descriptions of study feasibility, namely the study recruitment and retention. We also collected biochemical parameters, CRSBI, hospitalization rate, antibiotic use, and mortality. Demographic, nutritional, clinical, and laboratory data were collected at baseline, 3 and 6 months of each arm. The primary analysis population was defined as the per-protocol population who completed the trial including all lipid measurements.ResultsA total of 65 HPN patients were assessed, and 60 met the inclusion criteria for the study. Thirty-five percent (21/60) were randomized using a computer-generated random number sequence generator: 10 participants were randomized to receive SO first while 11 were randomized to receive MO first. At 13 months, 3/10 who received SO first completed the study, whereas 9/11 who received MO first completed the study. This did not meet our a priori criteria for success in recruitment and retention. Between types of lipid emulsions, there were no significant differences in changes in liver enzymes or biochemical and clinical outcomes, despite significant changes in plasma free fatty acid composition reflecting MO or SO.ConclusionsOverall, this pilot trial demonstrated that the use of a prospective double-blind, crossover, randomized trial design was not feasible to conduct in the HPN population because of difficulties in recruiting and retaining patients. In addition, there was no significant impact of MO versus SO lipid emulsion on liver enzymes or most parameters. The lack of significance may be attributed to low sample size from low recruitment and high drop-out rate, short study duration (6 months/arm), and complex care. In a future definitive trial, a multicenter study of longer duration and a larger sample size is recommended, and drop-outs may be reduced by using a parallel study design.Trial registrationClinicalTrials.gov, NCT02796833. Registered on 13 June 2016—retrospectively registered.

Development of mouse models with restricted HLA-B∗57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury

Flucloxacillin (FLX)-induced liver injury is immune-mediated and highly associated to HLA-B∗57:01 expression. Host factors leading to drug-induced liver injury are not yet well understood. Characterize invivo immune mechanisms determining the development of CD8+ T cells reactive to FLX in animals expressing the risk human leukocyte antigen (HLA) allotype. HLA-B∗57:01 transgenic mice (Tg) or Tg strains with H2-KbDb knockout (Tg/KO) or H2-KbDb/PD-1 double knockout (Tg/DKO) were treated with drug and/or anti-CD4 antibody. Drug-induced liver injury was evaluated on the basis of liver enzyme and histologic changes at day 10 of treatment. FLX-reactive CD8+ T cells were characterized invitro by release of effector molecules on drug restimulation, gene expression, and flow cytometry analysis, and functionality tested for hepatic cytotoxicity. CD8+ T-cell responses to FLX in Tg were dependent on both HLA and mouse major histocompatibility complex I presentation and invivo priming. Eliminating H2-KbDb in Tg/KO to allow exclusive presentation of FLX by HLA resulted in a less robust drug-specific CD8+T-cell response unless CD4+ cells, including regulatory T cells, were depleted. Treatment of Tg/KO with anti-CD4 antibody and FLX led to subclinical liver inflammation associated with an increase in PD1+CD8+ T cells in the lymphoid organs and liver. Impaired PD-1 expression in Tg/DKO led to liver histopathologic and transcriptional alterations but without hepatic enzyme elevations. Moreover, effector lymphocytes accumulated in the liver and showed FLX-dependent hepatic cytotoxicity invitro when tolerogenic liver cells were depleted. In our invivo models, FLX primes CD8+ T cells to recognize drug presented by HLA-B∗57:01 and murine major histocompatibility complex I. HLA-B∗57:01-dependent CD8+ T-cell reaction to FLX is limited by the presence of CD4+ cells, presumably regulatory T cells, and PD-1 expression. Tolerogenic hepatic cells limit clinical disease through PD-L1 or additional unexplored mechanisms.

Abstract 6297: Rationale for the development of a differentiated Trop2 ADC

Abstract Background: Trophoblast antigen 2 (Trop2) or Tumor-Associated Calcium Signal Transducer 2 (TACSTD2) is a transmembrane glycoprotein that is overexpressed in several solid tumor cancers. Antibody drug conjugate (ADC) targeting of Trop2 has been clinically validated. The Trop2 ADC Trodelvy® (also known as Sacituzumab govitecan/IMMU-132) is approved for therapy of TNBC and urothelial cancer, and Datopotamab DXd (DS-1062) is currently being tested in NSCLC. Peak Bio’s Thailanstatin suite of immunomodulatory linker-toxins (L-Ts) is a set of 7 related molecules with distinct ADC features that have been extensively characterized in vitro and in vivo as Her2 ADCs and is being used as a platform to generate a pipeline of potentially differentiated ADCs (AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1832). Results: M2.8 is a fully humanized Peak Bio antibody (Ab) that targets human Trop2 (hTrop2) with high binding affinity [Kd (M)= 8.97-09]. M2.8 was optimized for binding affinity and humanization relative to its parent M2.1 [Kd (M)= 1.78-08], and, both M2.1 and M2.8, display species-specificity for the human and cynomolgus monkey Trop2 proteins. When bound to hTrop2-positive cell lines, M2.1 and M2.8 can rapidly internalize and deliver an ADC payload. To identify the optimal release for therapeutic efficacy, we conjugated our family of L-Ts with hRS7 at a comparable drug-to-antibody ratio (DAR) of 4. Maximal tumor growth inhibition (TGI) was associated with the Trop2 ADCs that were conjugated via amine coupling to lysine residues using non-cleavable L-T L22, later renamed PH1. To determine the effect of antibody on TGI efficacy, different doses, and DARs of M2.1 PH1 ADC were compared to PH1 ADCs made from other Trop2 Abs. At low dose levels, M2.1 PH1 ADCs exhibited comparable TGI with hRS7 PH1, TINA PH1, and T6-16 PH1 ADCs, but exhibited significantly greater TGI than hRS7 SN38 (IMMU-132), suggesting that payload potency, rather than epitope, was important in targeting Trop2. The results also suggested that a PH1 DAR of 4 was sufficient to obtain 90% TGI with multiple anti-Trop2 Abs. M2.1 PH1 ADC was safely tolerated by cynomolgus monkeys at 3 and 6 mg/kg Q3W x 3 doses with mild-to-moderate changes in liver enzymes and platelets that reversed to baseline within 7-10 days of administration of each dose. The optimized M2.8 PH1 DAR4 ADCs killed Trop2-positive cell lines with single-digit nanomolar potency, while exhibiting low off-target cytotoxicity vs normal human skin fibroblasts and Trop2-negative cell lines in vitro. M2.8 PH1 ADC regressed all 200mm3 sized NCI-N87 tumors and 50% of these tumors exhibited long-term regression for 5 months. Conclusion: The target validation studies suggest that Trop2 PH1 ADCs were sufficiently differentiated in areas of preclinical efficacy and well tolerated in a toxicologically relevant host. Citation Format: Satyajit K. Mitra, William Monteith, Mary Do, Greg Tuffy, Scott Savage, Jeffrey Kang, Mastewal Abuhay, Teodora Losic, Sanjeevani Ghone, William E. Haskins, Vasu Jammalamadaka, Sanjeev Satyal. Rationale for the development of a differentiated Trop2 ADC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6297.

Changes in liver enzymes are associated with changes in insulin resistance, inflammatory biomarkers and leptin in prepubertal children with obesity

BackgroundNon-alcoholic fatty liver disease is associated with obesity. A subclinical inflammation state, endothelial dysfunction, and parameters related to metabolic syndrome (MetS), have been documented in children with obesity. We aimed to determine the changes that occur in liver enzymes levels in response to the standard treatment of childhood obesity, also assessing any associations with liver enzyme levels, leptin, and markers of insulin resistance (IR), inflammation, and parameters related to MetS in prepubertal children.MethodsWe carried out a longitudinal study in prepubertal children (aged 6–9 years) of both sexes with obesity; a total of 63 participants were recruited. Liver enzymes, C-reactive protein (CRP), interleukin-6, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), soluble intercellular adhesion molecule-1 (sICAM-1), leptin, homeostasis model assessment for IR (HOMA-IR), and parameters related to MetS were measured.ResultsAfter standard treatment for 9 months, children who lowered their standardised body mass index (SDS-BMI) had significantly lower systolic blood pressure (p = 0.0242), diastolic blood pressure (p = 0.0002), HOMA-IR (p = 0.0061), and levels of alanine aminotransferase (ALT) (p = 0.0048), CRP (p = 0.0001), sICAM-1 (p = 0.0460), and IL-6 (p = 0.0438). There was a significant association between the changes that occur with treatment, in the ALT levels, and changes in leptin (p = 0.0096), inflammation biomarkers [CRP (p = 0.0061), IL-6 (p = 0.0337), NLR (p = 0.0458), PLR (p = 0.0134)], and HOMA-IR (p = 0.0322).ConclusionOur results showed that a decrease in ALT levels after the standard treatment for 9 months was associated with favourable changes in IR markers (HOMA-IR) and inflammation (IL-6, CRP, NLR, and PLR).

Association of the changes in hepatic enzymes, bilirubin, and plasma proteins with beta-thalassemia in iron over loaded-patients

Changes in liver enzymes and bilirubin in patients with thalassemia depend on genetic changes and the association of other genetic determinants. Iron overload is associated with increased morbidity in both transfusion-dependent and non-transfusion-dependent thalassemia patients. The main objective was to evaluate hepatic enzymes, bilirubin and plasma proteins in βTM patients and also to study the correlations of these parameters with serum hemoglobin and ferritin concentrations in βTM patients. To achieve this goal, the study was directed on two groups, the first is case group includes 39 patients with βTM and the second control group includes 34 subject. Serum ALT, AST, total bilirubin, albumin and total protein concentrations were measured by UV-Vis Spectrophotometer, while the concentration of serum ferritin was measured by ELISA Kit. Our results showed that there are highly significant differences between beta thalassemia major and ferritin at mean (2942.71) , furthermore there are highly significant differences between beta thalassemia major and liver enzymes at (71.98) for AST , (69.42) for ALT, (6.98) for Total protein, (3.92) for Albumin and (2.32) for Total bilirubin. In addition our findings showed there are Correlations between serum ferritin concentrations and liver function testes in βTM patients, where there are highly significant differences between beta thalassemia major and Alanine transaminase at mean (r = 0.44), while the Correlation between serum hemoglobin concentration and liver function testes showed highly significant differences between beta thalassemia major and aspartate aminotransferase at mean (r = 0.52). The study concluded that the increase in serum liver enzymes (ALT, AST) and total bilirubin concentrations in patients with βTM are indicator to liver dysfunction that is correlated to iron overload.

O035 Elevated liver enzymes in paediatric sleep disordered breathing

Abstract Introduction Paediatric sleep disordered breathing (SDB) is associated with adverse cardiovascular outcomes. Non-alcoholic fatty liver disease (NAFLD) and dyslipidaemia are potential modifiable risk factors for cardiovascular disease, often coexisting in adults with SDB. Increases in lipid outputs from the liver have been identified in obese adults and children with SDB. Whether children with SDB compared to healthy non-snoring controls have evidence of elevated serum lipids and associated liver enzyme changes were assessed. Methods Seventy-five children (SDB=49, controls=26) between the ages of 6-17 years matched for age, gender and BMI underwent overnight polysomnography to measure SDB severity and provided a fasting blood sample to assess lipid and liver panels. Results OAHI was significantly increased in children with SDB compared to healthy non-snoring controls (p &amp;lt; 0.05). Serum potassium, alanine aminotransferase and lactate dehydrogenase were significantly increased in children with SDB, while albumin was significantly decreased (p &amp;lt; 0.05). No differences were found between serum lipid levels. Conclusion The presence of paediatric SDB may increase the risk of developing NAFLD. Further investigation is required to determine whether routine assessment of liver enzymes should be implemented in paediatric SDB. Whether surgical removal of the adenoids and tonsils to treat paediatric SDB can stabilise liver enzyme levels requires further research.

ODP190 Efficacy of Esaxerenone on Hypertensive Patients with Type 2 Diabetes or Those with Impaired Glucose Tolerance

Abstract Patients with diabetes may develop mineralocorticoid receptor (MR) related hypertension due to abnormal activation of MR, thusMR blocker (MRB) is used for the treatment of hypertensionin patients with diabetes. Although theselective MRB esaxerenone (Esax)approved for hypertension, the effectiveness of Esax in daily clinical practice has not provenin hypertensive patients with type 2 diabetes (T2D) or those withimpaired glucose tolerance (IGT). The aim of this study is to clarifythe efficacy of Esax in these patients. In this retrospective study, patientswho initiated Esax from May 2019 to February 2020 and thosewho initiated amlodipine (Amlo) were screened. After excluding patients with a history of hypersensitivity to these drugs, K &amp;gt; 5. 0 mEq/L at the baseline and severe renal dysfunction (eGFR &amp;lt; 30 mL/min/1.73m 2), and patients receiving potassium preparations, 35 and 70 patients were enrolled in the Esax and Amlo group, respectively. After propensity score matching with the parameters including gender, age, body mass index (BMI), concomitant use of angiotensin receptor blocker, systolic blood pressure (SBP), diastolic blood pressure (DBP), K, AST, ALT, TG and eGFR, finally each 24 cases were analyzed. Primary endpoints were changes (Δ) in SBP and DBP from the baseline to 6 months after the initiation of the drugs. Secondary endpoints comprised changes in liver enzymes and those in lipid metabolism markers. Unpaired t-test was used for statistical analysis. The dose of Esax and Amlo were 2.2±0.5 mg and 4.1±1.2 mg at the baseline, and 3.4±1.3 mg and 5.3±1.2 mg at 6 months, respectively. SBP was more decreased in the Esax group compared with the Amlo group (ΔSBP: -27± 20 mmHg vs -11± 14 mmHg, p&amp;lt;0. 05). DBP was not significantly different between the two groups (ΔDBP: -11± 10 mmHg vs -9± 14 mmHg). In the Esax group, ALT and TG were significantly decreased (ΔAST: -7.3 ± 11.5 U/L vs +0.9 ± 9.5 U/L, p&amp;lt;0. 05,ΔTG: -14.3 ± 51. 0 mg/dL vs +33.5 ± 59.4 mg/dL, p&amp;lt;0. 05), and HDL-C significantlyincreased (ΔHDL: +1.8 ± 6.1 mg/dL vs -3.8 ± 4.8 mg/dL, p&amp;lt;0. 05). Severeadverse events were not observed in any subjects. These results suggest the efficacy of Esax for controlling blood pressure as well as the plausible benefit in liver disease and lipid metabolism in hypertensive patients with T2D or IGT. Presentation: No date and time listed

Naltrexone for alcohol use disorder: Hepatic safety in patients with and without liver disease.

Naltrexone is an approved drug for management of alcohol use disorder (AUD), but data in patients with liver disease (LD) are limited. We aimed to evaluate the safety of naltrexone in those with LD. This is a retrospective cohort of adults with and without LD who were prescribed naltrexone for AUD from 2015 to 2019 in a safety-net setting. Naltrexone hepatic safety was determined by liver enzyme changes during and after compared to before naltrexone prescription as well as rates of subsequent hospitalization and death by Kaplan-Meier methods. Factors associated with hospitalization were examined by Cox regression. Of 160 patients prescribed naltrexone for AUD, 100 (63%) had LD and 47 (47%) of those with LD had cirrhosis (47% decompensated). The total cohort, LD, and cirrhosis groups had lower adjusted mean aspartate aminotransferase and alanine aminotransferase levels after versus before naltrexone prescription (p < 0.001). Two-year survival was 97.7% (95% confidence interval [CI], 84.6-99.7), 95.4% (95% CI, 82.8-98.8), 90.8% (95% CI, 73.5-97.0), and 81.3% (95% CI, 41.2-93.8) in those without LD, LD without cirrhosis, cirrhosis, and decompensated cirrhosis groups (p=0.46), respectively. Alcohol-related 2-year hospitalization rates were 8.2% (95% CI, 2.7-24), 27.7% (95% CI, 16.6-44.0), 40.5% (95% CI, 24.8-61.6), and 41.7% (95% CI, 23.3-66.6) for the groups without LD, LD without cirrhosis, cirrhosis, and decompensated cirrhosis (p=0.007), respectively. Independent predictors of subsequent hospitalization were LD, (hazard ratio [HR], 3.70; 95% CI, 1.19-11.51; p=0.02), cirrhosis (HR, 5.16; 95% CI, 1.69-15.75), and shorter duration (≤30 days) of naltrexone prescription (HR, 2.50; 95% CI, 1.l2-5.20; p=0.01). Conclusion: Naltrexone is safe to use in patients with underlying LD, including those with compensated cirrhosis. Although encouraging, more safety data are needed for those with decompensated cirrhosis.

Modification of the diabetes prevention program for the treatment of nonalcoholic fatty liver disease: A pilot study.

The Diabetes Prevention Program (DPP) is the gold standard lifestyle modification program that reduces incident type 2 diabetes mellitus. Patients with prediabetes and patients with non-alcoholic fatty liver disease (NAFLD) often share metabolic features; we hypothesized that the DPP could be adapted and used to improve outcomes in patients with NAFLD. NAFLD patients were recruited into a 1year modified DPP. Demographics, medical comorbidities, and clinical laboratory values were collected at baseline, 6 and 12months. The primary endpoint was change in weight at 12months. Secondary endpoints were changes in hepatic steatosis, metabolic comorbidities, and liver enzymes (per-protocol basis) and retention at 6 and 12months. Fourteen NAFLD patients enrolled; three dropped out before 6months. From baseline to 12months, hepatic steatosis (p=0.03), alanine aminotransferase (p=0.02), aspartate aminotransferase (p= 0.02), high-density lipoprotein (p=0.01) and NAFLD fibrosis score (p<0.001) improved, but low-density lipoprotein worsened (p=0.04). Seventy-nine percent of patients completed the modified DPP. Patients lost weight and had improvements in five out of six indicators of liver injury and lipid metabolism. NCT04988204.

Biological Effects of Hydrogen Water on Subjects with NAFLD: A Randomized, Placebo-Controlled Trial.

Non-alcoholic fatty liver disease (NAFLD) is a liver pathology affecting around 25% of the population worldwide. Excess oxidative stress, inflammation and aberrant cellular signaling can lead to this hepatic dysfunction and eventual carcinoma. Molecular hydrogen has been recognized for its selective antioxidant properties and ability to attenuate inflammation and regulate cellular function. We administered hydrogen-rich water (HRW) to 30 subjects with NAFLD in a randomized, double-blinded, placebo-controlled manner for eight weeks. Phenotypically, we observed beneficial trends (p > 0.05) in decreased weight (≈1 kg) and body mass index in the HRW group. HRW was well-tolerated, with no significant changes in liver enzymes and a trend of improved lipid profile and reduced lactate dehydrogenase levels. HRW tended to non-significantly decrease levels of nuclear factor kappa B, heat shock protein 70 and matrix metalloproteinase-9. Interestingly, there was a mild, albeit non-significant, tendency of increased levels of 8-hydroxy-2’-deoxyguanosine and malondialdehyde in the HRW group. This mild increase may be indicative of the hormetic effects of molecular hydrogen that occurred prior to the significant clinical improvements reported in previous longer-term studies. The favorable trends in this study in conjunction with previous animal and clinical findings suggest that HRW may serve as an important adjuvant therapy for promoting and maintaining optimal health and wellness. Longer term studies focused on prevention, maintenance, or treatment of NAFLD and early stages of NASH are warranted.

Elevated serum PAR-1 levels as an emerging biomarker of inflammation to predict the dengue infection severity.

The present study was designed to check the serum levels of protease-activated receptor (PAR-1) in patients during different phases of dengue severity. Moreover, a correlation between serum PAR-1 levels and hematological parameters, inflammatory cytokine levels, and liver functional changes was also determined. Based on the World Health Organization criteria, the study population was divided into: nonsevere dengue fever (DF; n = 30), severe dengue hemorrhagic fever (DHF; n = 19), and severe dengue shock syndrome (DSS; n = 11). The platelet count (PLT) and hematocrit (HCT) were analyzed using an automated hematology analyzer and liver function enzymes aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphate (ALP), bilirubin were checked by auto-analyzer using diagnostic kits. Moreover, the levels of inflammatory mediators C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-17 (IL-17), and PAR-1 were determined using respective ELISA kits. The HCT levels were elevated and platelet count decreased significantly during dengue complications (DHF andDSS) compared to the DF patients, while the levels of liver functional biomarkers AST, ALT, ALP, and bilirubin remained elevated in DHF and DSS groups than in the corresponding DF group. Similarly, the inflammatory cytokine levels of CRP, TNF-α, IL-6, and IL-17 in DHF and DSS subjects were markedly increased when observed against DF subjects. Notably, the PAR-1 levels were significantly elevated in DHF and DSS groups than in the DF group and positively correlated with changes in HCT levels, inflammatory biomarkers, and liver enzymes. Our findings conclude that PAR-1 levels persistently increased with the severity of the dengue infection and are strongly associated with various clinical manifestations. Thus, PAR-1 levels can be used as a diagnostic marker for assessing dengue severity.