Rise In Alanine Aminotransferase Research Articles

Alleviative effect of betaine against copper oxide nanoparticles-induced hepatotoxicity in adult male albino rats: histopathological, biochemical, and molecular studies

BackgroundCopper oxide nanoparticles (CuO-NPs) have gained interest due to their availability, efficiency, and their cost-effectiveness. Betaine is an essential methyl donor and takes part in various physiological activities inside the body; it is found to have protective and curative effects against various liver diseases. The present study aimed to evaluate the hepatotoxic effect of CuO-NPs on adult male albino rats and the ability of betaine to alleviate such hepatotoxicity.MethodsForty adult male albino Wister rats were grouped into 4 groups (10 rats/group): group I a negative control, group II (CuO-NPs) injected with CuO-NPs intra peritoneal by insulin needle (0.5 mg/kg/day), group III (betaine + CuO-NPs) administered betaine orally by gavage needle (250 mg/kg/day 1 h before CuO-NPs) and CuO-NPs (0.5 mg/kg/day) finally, group IV (betaine) administered betaine orally by gavage needle (250 mg/kg/day) for consecutive 28 days. Blood and liver samples were gathered and processed for biochemical, molecular, histopathological, and immunohistochemical investigations.ResultsGroup II displayed a marked rise in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and malondialdehyde (MDA) levels. Furthermore, there is an excessive upregulation of the inflammatory biomarkers interleukin1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). On the other hand, substantial reduction in glutathione (GSH) levels and significant downregulation at glutathione peroxidase (GPx) mRNA gene expression. Regarding the histopathological deviations, there were severe congestion, dilatation and hyalinization of blood vessels, steatosis, hydropic degeneration, hepatocytic necrosis, increased binucleation, degenerated bile ducts, hyperplasia of ducts epithelial lining, and inflammatory cells infiltration. Immunohistochemically, there was a pronounced immunoreactivity toward IL-1β. Luckily, the pre-administration of betaine was able to mitigate these changes. MDA was dramatically reduced, resulting in the downregulation of IL-1β and TNF-α. Additionally, there was a considerable rise in GSH levels and an upregulation of GPx. Histopathological deviations were substantially improved as diminished dilatation, hyalinization and congestion of blood vessels, hepatocytes, and bile ducts are normal to some extent. In addition, IL-1β immunohistochemical analysis revealed marked decreased intensity.ConclusionBetaine can effectively reduce the hepatotoxicity caused by CuO-NPs via its antioxidant properties and its ability to stimulate the cell redox system.

In-vivo investigation of dimethoate toxicity on serum enzymes, target organs and intestinal tissues of albino rats

Dimethoate is a broad spectrum organophosphate insecticide used to control agricultural, industrial and domestic pests. Despite its benefits, toxicities in non-target organisms have been widely reported. This study investigated acute and sub-chronic toxicities of dimethoate in rats. The arithmetic method of Karbar and a modification of repeated 8-week oral toxicity were adopted for the determination of acute and sub-chronic toxicities of dimethoate, respectively. Symptoms of acute toxicity evaluated include muscular weakness, respiratory distress, convulsion and death. Animals that were used for the sub-chronic toxicity studies were divided into 4 groups of 5. Groups 2, 3 and 4 were fed with feeds containing 200, 500 and 800 mg/kg dimethoate respectively, while group 1 served as the control. The weight of the animals were determined weekly for 8 weeks, and thereafter sacrificed. Blood samples were collected for biochemical tests, and the liver, kidney, lung, intestine and heart were excised and processed for histopathological analysis. The calculated median lethal dose (LD50) was 176 mg/kg. Animals in all groups gained weight progressively. However, a dose-dependent significant rise in alanine transaminase and alkaline phosphatise, but not aspartate transaminase accompanied with significant focal necrosis in liver, eosinphilic casts in kidney and intestinal ulceration in group 3 and 4 in animals. In addition, dimethoate- induced inflammation was observed in the liver, kidney, lung and intestine tissues. The derangement of biochemical parameters and relevant histopathological alterations observed in rats exposed to dimethoate are suggestive of toxicity. Therefore necessary precautionary measures should be taking during handling and use.

Clinical Characteristics and Outcomes of Patients With Antithyroid Drug-Related Liver Injury.

Antithyroid drugs (ATDs) are the cornerstone of hyperthyroidism management. Hepatotoxicity due to ATDs can range from mild transaminase elevation to liver transplantation requirement and mortality. The primary objective of the systematic review was to assess the clinical characteristics and outcomes of patients with drug induced liver injury (DILI) due to ATDs. We conducted a systematic review of PUBMED, SCOPUS, and EMBASE on characteristics and outcomes of adults (>18 years) with DILI due to ATDs. We defined DILI as bilirubin ≥2.5 mg/dL or international normalized ratio >1.5 with any rise in alanine aminotransferase (ALT), aminotransferase (AST), or alkaline phosphatase (ALP), or an elevation of ALT or AST >5 times or ALP >2 times the upper limit of normal without jaundice/coagulopathy. The review included 100 articles describing 271 patients; 148 (70.8%) were female (N = 209). Mean age was 42.9 ± 17.2 years. Graves' disease was the most common indication for ATDs. Carbimazole/methimazole (CBM/MMI) was the most common offending agent (55.7%). DILI pattern was hepatocellular in 41.8%, cholestatic in 41.3%, and mixed in 16.9%. Outcomes included death in 11.8%, liver transplantation in 6.4%, partial improvement in 2.2%, and complete resolution in 79.6% with a median time (IQR) to resolution of 45 (20-90) days. Patients in the propylthiouracil (PTU) group had higher initial bilirubin, initial AST, initial ALT, peak ALT, peak AST, severe and fatal DILI, liver transplantation, and mortality than CBM/MMI. Rechallenge of antithyroid medication was infrequently reported (n = 16) but was successful in 75%. DILI due to ATDs can present with different patterns and should prompt immediate drug discontinuation. Referral to a hepatologist should be considered if severe as transplantation is sometimes required. PTU-induced DILI may have worse outcomes than CBM/MMI.

Rise in alanine aminotransferase after HCV treatment is a highly sensitive screen for treatment failure.

Nucleic acid testing to confirm sustained virological response (SVR) after HCV therapy is technical, often expensive, and frequently unavailable where disease prevalence is highest. Alternative surrogate biomarkers merit evaluation. In a short-treatment trial in Vietnam (SEARCH-1; n = 52) we analysed how changes in alanine transaminase (ΔALT) and aspartate transaminase (ΔAST), from end of treatment (EOT) to EOT + 12 weeks, related to SVR, defined as HCV RNA < lower limit of quantification 12 weeks after EOT. In a separate UK trial (STOPHCV1; n = 202), we then tested the hypothesis that any elevation in ALT or AST between EOT and EOT12 is a sensitive screen for treatment failure. In SEARCH-1, among 48 individuals with data, 13 failed to achieve SVR. Median ΔALT and ΔAST were negative in cured patients but elevated when treatment failed [median ΔALT (IQR): -2 IU/L (-6, +2)] versus +17 IU/L (+7.5, +38) (p< 0.001). Amongst treatment failures, 12/13 had increase in ALT and 13/13 had increase in AST after EOT, compared with 12/35 in those cured. In STOPHCV1, 196/202 patients had evaluable data, of which 57 did not achieve SVR. A rise in ALT after EOT was 100% sensitive (95% C.I. [93.7 - 100%]) and 51% specific (42.4 - 59.7%) for detecting treatment failure. ΔAST >0 IU/L was 98.1% (89.9 - 99.9%) sensitive and 35.8% (27.3 - 45.1%) specific. A rise in ALT or AST after HCV therapy is a highly sensitive screen for treatment failure in mild liver disease. This finding could reduce costs and complexity of managing HCV.

Efficacy and Safety of an Investigational Single-Course CRISPR Base-Editing Therapy Targeting PCSK9 in Nonhuman Primate and Mouse Models.

VERVE-101 is an investigational in vivo CRISPR base-editing medicine designed to alter a single DNA base in the PCSK9 gene, permanently turn off hepatic protein production, and thereby durably lower low-density lipoprotein cholesterol. We test the efficacy, durability, tolerability, and potential for germline editing of VERVE-101 in studies of nonhuman primates and a murine F1 progeny study. Cynomolgus monkeys were given a single intravenous infusion of a vehicle control (n=10) or VERVE-101 at a dose of 0.75 mg/kg (n=4) or 1.5 mg/kg (n=22) with subsequent follow-up up to 476 days. Two studies assessed the potential for germline editing, including sequencing sperm samples from sexually mature male nonhuman primates treated with VERVE-101 and genotyping offspring from female mice treated with the murine surrogate of VERVE-101 (VERVE-101mu). Liver biopsies 14 days after dosing noted mean PCSK9 editing of 46% and 70% in monkeys treated with VERVE-101 at 0.75 and 1.5 mg/kg, respectively. This translated into mean reductions in blood PCSK9 (proprotein convertase subtilisin/kexin type 9) of 67% and 83% and reductions of low-density lipoprotein cholesterol of 49% and 69% at the 0.75 and 1.5 mg/kg doses, respectively, assessed as time-weighted average change from baseline between day 28 and up to 476 days after dosing. Liver safety monitoring noted a transient rise in alanine aminotransferase and aspartate aminotransferase concentrations after infusion that fully resolved by day 14 with no accompanying change in total bilirubin. In a subset of monkeys necropsied 1 year after dosing, no findings related to VERVE-101 were identified on macroscopic and histopathologic assessment of the liver and other organs. In the study to assess potential germline editing of male nonhuman primates, sperm samples collected after VERVE-101 dosing showed no evidence of PCSK9 editing. Among 436 offspring of female mice treated with a saturating dose of VERVE-101mu, the PCSK9 edit was transmitted in 0 of 436 animals. VERVE-101 was well tolerated in nonhuman primates and led to 83% lower blood PCSK9 protein and 69% lower low-density lipoprotein cholesterol with durable effects up to 476 days after dosing. These results have supported the initiation of a first-in-human clinical trial in patients with heterozygous familial hypercholesterolemia and atherosclerotic cardiovascular disease.

Clinical effects and safety of different transarterial chemoembolization methods for bridging and palliative treatments in hepatocellular carcinoma

PurposeWe assessed and compared clinical effects and safety endpoints of three methods of transarterial chemoembolization (TACE), conventional (cTACE), with drug-eluting beads (DEB-TACE), and with degradable starch microspheres (DSM-TACE), used in patients with hepatocellular carcinoma (HCC) in the bridging to liver transplant (LT) and the palliative setting.MethodsIn our center, 148 patients with HCC underwent 492 completed TACE procedures between 2008 and 2017 (158 for bridging to LT; 334 for palliative treatment) which we analyzed retrospectively. Of these procedures, 348 were DEB-TACE, 60 cTACE, and 84 DSM-TACE.ResultsThe cTACE procedure revealed a significantly longer period of hospitalization (p = 0.02), increased occurrence of nausea (p = 0.025), and rise in alanine transaminase (ALT) levels (p = 0.001), especially in the palliative setting. In the bridging to LT cohort, these clinical endpoints did not reach statistical significance.ConclusionsThe clinical safety of different TACE methods for HCC in both the palliative and the bridging to LT setting was equivalent. In the palliative setting, the cTACE procedure revealed an increased risk for adverse clinical effects such as nausea, elevation of ALT, and a prolonged period of hospitalization what might either be related to the systemic effects of the chemotherapeutic agent or to the differences in both collectives. Thus, further studies must be conducted on a larger number of TACE procedures to effectively explore the clinical side effects of the various TACE variants.

Evaluation of Liver Enzymes and calculation of AST to ALT ratio in patients with acute viral hepatitis

Background: Acute viral hepatitis is a common liver-associated abnormality encountered in clinical practice. The number of biochemical parameters is estimated to detect a hepatic abnormality, which can measure the severity and types of damage to hepatocytes, among which liver enzymes and bilirubin levels are assessed routinely which are raised in acute viral hepatitis.Objective: This study aims to assess the liver enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin, and calculation of AST to ALT ratio in acute viral hepatitis and to compare these parameters with the control group.Methodology: This study included a total of 81 subjects diagnosed with acute viral hepatitis as cases and age and sex-matched, the same number of healthy subjects as control. Serum levels of AST and ALT, alkaline phosphatase (ALP), and bilirubin were analyzed using standard methods. Serum AST to ALT ratio was calculated. Data analysis was done using SPSS Version 17.0 and the results were expressed as mean ±standard deviation (SD).Results: A mean serum activities of aminotransferases were statistically significantly raised in viral hepatitis compared to that in control.AST (514.85±350.66 VS 25.65±5.29; p&lt;0.001) and ALT (781.65±525.69 VS 27.94±6.50; p&lt;0.001). Similarly, serum levels of(ALP)were significantly increased in acute viral hepatitis compared to that in control (202.17±75.46 VS 98.83±27.99; p&lt;0.001. However, a ratio of AST to ALT was decreased significantly (0.66±0.15 VS 0.94±0.21; p= 0.001) in acute viral hepatitis compared to that in control.Conclusion: Both the aminotransferases and bilirubin levels are raised significantly, where, a rise in ALT is greater than a rise in AST, hence, the ratio of AST to ALT is decreased significantly in acute viral hepatitis than that in control. Thus, this decreased pattern of AST to ALT can diagnose acute viral hepatitis at an early stage and can help appropriate care and treatment to the patients.

Prevalence and Characteristics of Gastrointestinal Symptoms and Hepatic Manifestation in Covid-19 Infection in Tertiary Care Center

Introduction: Although the primary clinical manifestation of COVID-19 is pulmonary disease, but there are increasing data to support the gastrointestinal and hepatic involvement. Aims: We aimed to see the prevalence and characteristics of gastrointestinal symptoms and hepatic manifestation in COVID-19 infection. Methods: This is a hospital based descriptive cross-sectional study which was carried out in medicine department of Nepalgunj Medical College. Consecutive patients of COVID-19 cases confirmed by polymerase chain reaction were included. The presenting complaints, laboratory parameters, clinical events were noted. The primary objective was to determine the prevalence of gastrointestinal manifestation and hepatic dysfunction and their correlation with severity of pneumonia. Results: Total patients enrolled in the study were 205. Majority of patients presented with respiratory symptoms 67.8%. Both respiratory and gastrointestinal symptoms were observed in 29.3% cases. Isolated gastrointestinal symptoms were observed in 2.9% cases. Common gastrointestinal symptoms were anorexia 14.1%, anorexia and nausea in 6.3%, pain abdomen in 3.9% and diarrhea in 2.4% cases. Hepatocellular type hepatic dysfunction reported in 53.2% cases. Rise in alanine aminotransferase (58.2% vs. 23.6%), aspartate aminotransferase (51.6% vs. 20.6%), alkaline phosphatase (44% vs. 15%), total bilirubin (76.6% vs12.5%) found significantly high in severe pneumonias compared with pneumonia only. Both gastrointestinal and hepatic dysfunctions were more common in severe cases (87.9% and 58.7%) than in mild disease (1% and 27%). Conclusion: One third of the patients of COVID-19 can have gastrointestinal symptoms and hepatic dysfunction. Around 3% of patients presented with isolated gastrointestinal symptoms. Thus, unexplained gastrointestinal symptoms in contacts of COVID-19 may demand polymerase chain reaction test to confirm the disease. Both gastrointestinal and hepatic dysfunction was more prevalent in severe pneumonia.

Role of anti-HBs in functional cure of HBeAg+ chronic hepatitis B patients infected with HBV genotype A

HBsAg-specific antibody responses are difficult to detect during chronic hepatitis B infection (CHB) and are often overlooked. The aim of this study was to examine whether anti-HBs may be involved in functional cure (FC) by profiling anti-HBs responses in patients with CHB using a panel of specific assays. Longitudinal serum samples were obtained from 25 patients with CHB who were infected with HBV genotype A and were undergoing nucleos(t)ide analogue (NA) treatment: 14 achieved FC while 11 remained infected (non-FC). Anti-HBs immune complexes (HBsAg-IC), FcγRIIIa dimer binding, epitope specificity and neutralisation efficacy were measured. HBsAg-IC peaks were detected prior to HBsAg loss in 10/14 FC patients. These HBsAg-IC peaks overlapped with either an alanine aminotransferase (ALT) flare (8/10 patients), or a rise in ALT (2/10 patients). HBsAg-IC peaks were detected in 7/11 non-FC patients, but were not associated with an ALT flare. FCγRIIIa binding was detected in 9/14 FC patients, independent from detection of overlapping HBsAg-IC/ALT peaks. FC patients had stable HBsAg epitope occupancy across the study, whereas non-FC patients had a reduction in HBsAg epitope occupancy within the first 12-24 weeks of NA treatment. Convalescent sera from FC patients recognised more HBsAg epitopes and neutralised HBV infection more potently than anti-HBs derived from vaccinees. Neutralisation potency appeared to increase post-HBsAg loss in 4/5 FC patients examined. Using these assays, we confirm that anti-HBs responses are present and fluctuate over time in this cohort of patients with HBeAg+ CHB, who were infected with HBV genotype A and treated with NAs. Key anti-HBs profiles associated with either FC or failure to achieve FC were also identified, suggesting a role for anti-HBs responses in FC. Using a panel of assays to characterise hepatitis B surface antibody (anti-HBs) responses in a group of patients with chronic hepatitis B, we identified anti-HBs profiles associated with either functional cure, or failure to achieve functional cure. Functional cure was associated with immune complex peaks which overlapped with alanine aminotransferase flares. Conversely, in those who did not achieve functional cure, immune complex peaks were present, but were not associated with alanine aminotransferase flares, and a decline in anti-HBs diversity was observed early during treatment.

101HEMB01 Is a Phase 1/2 Open-Label, Single Ascending Dose-Finding Trial of DTX101 (AAVrh10FIX) in Patients with Moderate/Severe Hemophilia B That Demonstrated Meaningful but Transient Expression of Human Factor IX (hFIX)

▪Background: Gene transfer is expected to be an effective therapy for hemophilia B because the disease is caused by mutations in a single gene. DTX101 is a non-replicating recombinant adeno-associated virus (AAV) serotype rh10 (AAVrh10) vector that contains a codon-optimized hFIX gene with expression driven by both a liver-specific enhancer element and a liver-specific promoter element. AAVrh10 is a clade E virus with high degree of homology to AAV8.Aims: To determine the safety and efficacy of single, ascending doses of DTX101 in hemophilia B patients.Methods: 101HEMB01 is a phase 1/2 open-label, single-arm, multicenter, dose-finding study. Eligible subjects (Inclusion criteria: Male ≥18 years, baseline FIX ≤2%; Exclusion criteria: anti-AAVrh10 neutralizing antibody titer >1:5) received a single IV infusion of DTX101. Safety assessments included incidence of adverse events (AEs). Efficacy assessments included change from baseline in FIX activity, annualized bleeding rate and annualized use of FIX replacement therapy.Results: 6 subjects were dosed. Subjects in Cohort 1 (n=3) and Cohort 2 (n=3) received a dose of DTX101 of 1.6×1012 Genome Copies (GC)/kg and 5.0×1012 GC/kg, respectively. All subjects have been followed ≥32 weeks. Peak FIX levels in Cohort 1 were achieved between 8 and 14 weeks and ranged from 5% - 11%. Peak FIX levels in Cohort 2 ranged from 12% - 20% and were reached between 3 and 8 weeks. An asymptomatic rise in alanine aminotransferase (ALT) level was observed at approximately the time of peak FIX level and was followed by a gradual reduction in FIX level to near baseline in all but one subject, despite initiation of a steroid treatment protocol. Peak ALT values were considered either Grade 1 or 2 AEs in 4 subjects (≤3.0 or ≤5.0 x upper limit of normal, respectively). Subject 6 had a peak ALT 914 U/L and was considered a Grade 4 AE. Steroid protocol was initiated with normalization of ALT levels. Subjects 4 and 5 had subsequent mild rises in ALT following completion of the steroid protocol with additional loss in FIX activity. No subject developed FIX inhibitors. Bleeding events and use of FIX replacement therapy data are currently being analyzed.Conclusion: Study 101HEMB01 clearly demonstrated evidence of FIX expression following a single injection of DTX101 (peak FIX 5% - 20%); however, FIX levels were not sustained. The loss in FIX levels may be related to AAVrh10 capsid-induced immune response; Dimension Therapeutics has ongoing studies to better understand this response (ASH 2017 abstract submission: R. Calcedo, Immune responses in 101HEMB01, a phase 1/2 open-label, single ascending dose-finding trial of DTX101 (AAVrh10FIX) in patients with severe hemophilia B). The 6 subjects dosed in study 101HEMB01 will continue to be closely followed for a total of 5 years in the extension study (101HEMB02). Insights from these data support continued development of other AAV gene therapy programs. DisclosuresPipe:Bayer Healthcare; Biogen Idec; CSL Behring; Dimension Therapeutics; Novo Nordisk; Roche; Shire; uniQure: Consultancy; Shire; Siemens Healthcare Diagnostics Inc.: Research Funding. Poma:Dimension Therapeutics: Employment, Equity Ownership. Crombez:Dimension Therapeutics: Employment, Equity Ownership.

Protective effect of vitamin D in mice with acute liver failure

Objective: To explore the protective effect of vitamin D in acute liver failure through a mouse model. Methods: Acute liver failure was induced by combining D-galactosamine (D-GalN) lipopolysaccharide (LPS) to observe the effect of long-term vitamin D deficiency on liver injury and inflammatory signals in a mouse model. Acute liver failure was induced by thioacetamide (TAA) to observe the effect of vitamin D deficiency on the survival rate, and further high-dose of vitamin D supplementation protective effect was determined in a mouse model. Liver function was evaluated by measuring serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and liver inflammation by hematoxylin-eosin staining. The expressions of tumor necrosis factor (TNF-α), interleukin (IL) -1β, NOD-like receptor family, pyrin domain containing 3 (NLRP-3), chemokines (CCL2, CXCL1 and CXCL2), etc. in liver tissues were detected by RT-qPCR. The quantitation of macrophages in liver tissue was detected by immunohistochemistry. The comparison between groups were performed by t-test. The survival curve was analyzed by log-rank (Mantel-Cox) test. Results: Long-term vitamin D deficiency had increased acute liver failure sensitivity in mice, which was manifested by increased blood cell extravasation, massive necrosis of parenchymal cells, up-regulation of TNF-α, IL-1β, and NLRP-3 mRNA expression (P < 0.05), and increased macrophages quantitation (P < 0.05) in liver tissues. At the same time, vitamin D deficiency had increased the mice mortality rate because of liver injury (P < 0.01). On the contrary, pre-administration of high dose of vitamin D (100 IU/g) had significantly reduced liver injury, inhibited ALT and AST rise (P < 0.01), alleviated liver necrosis, and down-regulated the mRNA expression of inflammatory factors in liver tissues (P < 0.05). Conclusion: Mouse model shows that long-term vitamin D deficiency can aggravate drug-induced acute liver failure and reduce survival rates. Furthermore, high-dose of vitamin D has a certain hepatoprotective effect, which can significantly improve liver necrosis condition and inhibit inflammation. Therefore, adequate vitamin D can retain liver physiological balance to resist liver injury.

HepatocyteGHR/STAT5b Signaling Protects Against Liver Injury in NAFLD/NASH Mice Models Independent of Steatosis

Non-alcoholic fatty liver disease (NAFLD) represents a spectrum of pathologies ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) that can lead to cirrhosis and hepatocellular carcinoma. Clinical and mouse studies indicate GH-signaling is reduced in NAFLD. We reported that chow-fed mice, with adult-onset, hepatocyte-specific GH receptor knockdown (aHepGHRkd) develop steatosis, and with age, a mild NASH-like phenotype. In the present study, we sought to determine if aHepGHRkd accelerates the development of steatosis and fibrosis in the context of diets shown in wild-type male mice, after 6 months of feeding, to produce mild NASH (60% fat [lard] + sucrose in the drinking water [HFS] or a severe NASH-like phenotype (40% fat, with partially hydrogenated corn-oil; 2% cholesterol; 20% fructose [HFCF]). Since aHepGHRkd is associated with a reduction in active STAT5b, aHepGHRkd mice were treated with either a hepatocyte-specific adenoviral-associated vector that expresses constitutively active STAT5b (AAV-TBGp-STAT5bCA = STAT5bCA) or a AAV-Null vector. After only 3 months of feeding either the HFS or HFCF diet, aHepGHRkd, but not GHR-intact controls, mice exhibited clear fibrosis, associated with higher levels of plasma alanine aminotransferase (ALT). STAT5bCA treatment of aHepGHRkd mice reduced fibrosis, as well as plasma ALT. Of note, hepatic TG content did not differ between the treatment groups, within diet. Preliminary studies used GC-MS to reveal aHepGHRkd, in the context of HFS diet, increased hepatic fatty acid ratios indicative of enhanced de novo lipogenesis, while STAT5bCA reversed this effect. These results suggest GHR/STAT5b may protect against liver injury not by controlling absolute fat accumulation, but by modifying the fatty acid composition of hepatic lipids. Finally, in order to determine if STAT5bCA could also reverse established diet-induced NASH, wild-type mice were fed the HFCF diet for 6 months and then treated with AAV-STAT5bCA or AAV-Null vectors, and followed for an additional 3 months. Preliminary findings show STAT5bCA modestly reduced liver weight with no changes in TG content. However, STAT5bCA prevented the rise in plasma ALT observed in Null-treated controls. Of note, some mice developed hepatic tumors, where the number and size of visible tumors was reduced by STAT5bCA. Importantly, in all models examined thus far, changes in the liver phenotype could not be clearly attributed to changes in systemic metabolism, supporting a direct action of GHR/STAT5b signaling on liver health. Taken together, these results suggest that enhancing hepatocyte STAT5b activity could prevent/treat diet-induced NASH. How STAT5b mediates these effects, and if there are other players involved, remains to be elucidated.

Biochemical Study of Some Parameters in Patients with B- Thalassemia in Karbala City

This study is intended to estimate some biochemical parameters in the adult men with ß- thalassemiamajor and compared with control group. Twenty Iraqi beta- thalassemia major (TM) patients are employedfrom thalassemia center in Karbala city at age of 15-25 years . The body mass index (BMI) of patients wascalculated by measuring weight and high of patients , and the concentration of platelets ,Total cholesterol(TC),Triglyceride(TG),Low density lipoprotein (LDL) ,high density lipoprotein(HDL), Alanine aminotransferase (ALT), Aspartate transferase (AST), Antidiuretic hormone (ADH),Growth hormone (GH),Triiodothyronine (T3) ,Thyroxin (T4), Thyroid stimulating hormone (TSH),Testosterone hormone, Ureaand Creatinine were measured in thalassemic patients and compared with healthy control group. Theresults display that significant decrease (p&lt;0.05) in serum levels platelets, HDL, ADH, GH, TSH, T3, T4,Testosterone hormones and creatinine in patients with ß- thalassemia and showed significant rise (p&lt;0.05)in serum Tc, TG, LDL, ALT, AST and Urea levels in thalassemic group compared with healthy group .andthe results demonstration that significant lower in BMI in group of patients compared with control group.we can be concluded from the present study ,that iron overload state influence on some endocrine glandssecretions, liver and kidney functions.

Carbon Tetrachloride-Induced Hepatocellular Damage in Balb C Mice and Pharmacological Intervention by Extract of Daucus Carota

Background: Present research was planned to examine the shielding effect of Daucus carota root extract pre-treatment on the carbon tetrachloride-induced hepatotoxicity in Balb C mice.&#x0D; Objective: To cover the assessment of the enzymatic activity such as Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) and biochemical constituents like cholesterol, protein, lipids, glucose and urea contents in both the blood and liver while RNA and DNA substances exclusively in the liver.&#x0D; Setting: The induction of carbon tetrachloride (CCl4)-induced hepatotoxicity caused a rise in ALT of plasma and a decline in LDH.&#x0D; Method: The mice were treated with CCl4 and Daucus carota extract to check their effect on the level of biochemical constituents.&#x0D; Main Outcome Measure: Daucus carota extract pre-treatment obliterated CCl4-induced variations in the actions of enzymes.&#x0D; Results: cholesterol content decreased while glucose level increased in the blood. Glucose, lipids, cholesterol and urea in the liver were reduced while total protein level rose. Daucus carota extract pre-treatment also prohibited CCl4-induced variations in total protein contents, urea, glucose and lipids in the liver. CCl4 action caused huge hepatic damage. This was averted by Daucus carota extract.&#x0D; Conclusion: These outcomes reveal that Daucus carota root extract pre-treatment inhibited hepatic damage induced by CCl4 in the mice model, which corroborates its defensive effects against hepatic damage produced by both non-oxidative and oxidative mechanisms.

Changes in alanine aminotransferase in adults with severe and complicated obesity during a milk-based meal replacement programme

IntroductionExcess adiposity is associated with fat accumulation within the liver, and non-alcoholic steatohepatitis (NASH) is highly prevalent in bariatric patients. Elevated alanine aminotransferase (ALT) is associated with prevalent NASH. We sought to determine the influence of a milk-based meal replacement weight-loss programme on ALT levels in adults with severe and complicated obesity.MethodsWe conducted a retrospective cohort study of patients who completed a 24-week meal replacement programme, comprised of a weight loss phase followed by weight stabilisation and maintenance phases, each 8 weeks long. ALT was quantified using an enzymatic assay with spectrophotometric detection. We examined changes over time in ALT using the non-parametric Wilcoxon singed-rank test and the Friedman test.ResultsOf 105 patients, 56 were female, mean age was 51.2 ± 11.2 (range 18.0–71.6) years. There was an unanticipated but transient increase in ALT from 28.0 [20.0, 40.5] iu/L at baseline to 40.0 [26.0, 55.0] iu/L after 2 weeks (p < 0.0005), followed by a gradual reduction to 21.0 [17.0, 28.3] iu/L by 24 weeks (p < 0.0005). The overall reductions in ALT were more pronounced in patients who had elevated levels at baseline. Body weight decreased from 144.2 ± 28.0 kg at baseline to 121.6 ± 25.4 kg at 24 weeks (p < 0.0005) and body mass index (BMI) decreased from 50.7 ± 8.1 kg m−2 at baseline to 43.0 ± 7.6 kg m−2 by 24 weeks (p < 0.0005).ConclusionIn adults with severe and complicated obesity undergoing a milk-based meal replacement programme, there was an initial unanticipated rise in ALT in the first 2 weeks, followed by a gradual overall reduction by 24 weeks. These findings suggest that rapid weight loss secondary to significant caloric restriction might induce a transient deterioration in hepatic steatosis prior to an ultimate overall improvement.

Single-Dose Pharmacokinetics and Preliminary Safety Assessment with Use of CBD-Rich Hemp Nutraceutical in Healthy Dogs and Cats.

Simple SummaryThe use of cannabidiol (CBD)-rich hemp-based nutraceuticals is increasing in dogs and cats for disorders related to anxiety, seizures, cancer and pain. To date, there is little information related to appropriate dosing or long-term effects on serum chemistry or complete blood counts (CBC), and little data on the pharmacokinetics of single- or long-term dosing in dogs and cats. Single-dose pharmacokinetics and preliminary 12-week serum chemistry and complete blood counts are reported here showing short pharmacokinetic half-lives of cannabidiol in dogs and cats, with cats showing far lower oral absorption kinetics or rapid elimination suggesting dosing may differ between the two species. Fortunately, there were no changes in physical examination and few changes in the CBC and serum chemistry parameters suggesting the relative safety of oral supplementation over 12 weeks. One of the eight cats displayed a persistent rise in the serum alanine amino transferase (ALT) enzyme outside of the reference range and cats commonly displayed excessive licking and head shaking with administration of the oil. Based on these and other recent data, CBD-rich hemp nutraceuticals appear to be safe in healthy adult dogs, while more work in cats is needed to fully understand utility and absorption.The use of CBD-rich hemp products is becoming popular among pet owners with no long-term safety data related to consumption in adult dogs and cats. The purpose of this study was to determine the single-dose oral pharmacokinetics of CBD, and to provide a preliminary assessment of safety and adverse effects during 12-week administration using a hemp-based product in healthy dogs and cats. Eight of each species were provided a 2 mg/kg total CBD concentration orally twice daily for 12 weeks with screening of single-dose pharmacokinetics in six of each species. Pharmacokinetics revealed a mean maximum concentration (Cmax) of 301 ng/mL and 43 ng/mL, area under the curve (AUC) of 1297 ng-h/mL and 164 ng-h/mL, and time to maximal concentration (Tmax) of 1.4 h and 2 h, for dogs and cats, respectively. Serum chemistry and CBC results showed no clinically significant alterations, however one cat showed a persistent rise in alanine aminotransferase (ALT) above the reference range for the duration of the trial. In healthy dogs and cats, an oral CBD-rich hemp supplement administered every 12 h was not detrimental based on CBC or biochemistry values. Cats do appear to absorb or eliminate CBD differently than dogs, showing lower serum concentrations and adverse effects of excessive licking and head-shaking during oil administration.

2348 A Rare Case of Biktarvy-Induced HBV Flare

INTRODUCTION: Exacerbation of chronic hepatitis B virus (HBV) is defined as an acute rise in alanine aminotransferase (ALT) more than five times the upper limit of normal. Flare-ups of chronic HBV and human immunodeficiency virus (HIV) coinfection receiving antiretroviral therapy is seldom due to discontinuation or initiation of emtricitabine treatment. Here, we present a rare case of reinitiation of Biktarvy causing HBV flare. CASE DESCRIPTION/METHODS: A 53-year-old male presented to the emergency department from infectious disease clinic for worsening transaminitis, nausea and right upper quadrant (RUQ) pain for two days. Patient did not report any alcohol, supplement or acetaminophen use. Past medical history is significant for HIV and chronic HBV. He had been non-adherent to Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) for months and was restarted on the medication three weeks prior to presentation. His vitals were within normal limits. Physical examination revealed RUQ tenderness. Complete blood count showed platelet count of 137K. Coagulation study, basic metabolic panel, lipase were within normal limits. HBV Viral load: 7,126,237, HIV Viral load: undetectable, aspartate aminotransferase (AST): 599, ALT: &gt;680. Hepatitis panel showed immunity to Hepatitis A, Hepatitis C: negative, HBV surface antigen: positive, HBV core IgM: positive and no seroconversion of Hep Be antigen to antibody. All viral serologies, HIV, HBV status and transaminases listed in Tables 1 and 2 from former and current admission. Autoimmune and hereditary conditions work up done during current admission were negative (Table 3). RUQ ultrasound was unremarkable. Patient was seen in clinic two weeks later and reported adherence with Biktarvy. Liver enzymes continued to trend down and his symptoms of nausea and RUQ pain subsided. DISCUSSION: Emtricitabine is one of the components of HIV regimen of Biktarvy. Treatment flares due to emtricitabine arise only in 5-10% of patients and are usually asymptomatic. Our patient had symptomatic hepatotoxicity after restarting Biktarvy over the span of three weeks. Hepatotoxicity could be due to the variations of viral replication activating immune responses. Even though the flare ups of chronic HBV can be due to initiation of emtricitabine, it is recommended to continue the agent and monitor for down trending pattern of aminotransferases which was depicted in our case.

Prescription Audit of Anti-fungal Treatment of Dermatophytoses in the Dermatology Out Patient Department of a Tertiary Care Hospital

Aims: To study the prescriptions of clinically diagnosed cases of dermatophytoses, to evaluate medical treatment of clinical failure cases, any rise in serum ALT (Alanine aminotransferase) levels associated with usage of oral anti-fungal drugs, availability of drugs in the hospital pharmacy and cost minimization of different oral treatment regimens with Griseofulvin, Fluconazole, Itraconazole and Terbinafine. Settings and design: Dermatology Out Patient Department (OPD) of a tertiary care hospital, single centre prospective cohort observational study. Materials and Methods: 370 patients from the Dermatology Out Patient Department (OPD) diagnosed of dermatophytoses were enrolled. Follow-up was done 3±1 weeks apart, twice for newly diagnosed patients and once for patients on ongoing therapy. Two separate blood samples were collected 3±1 weeks apart for estimation of serum ALT. The prime lesion in each patient was graded as mild, moderate and severe. Patients were categorized as clinically cured, clinically improved, or as clinical failure following treatment. Statistical analysis used: Descriptive statistics, Fischer’s exact test and Wilcoxon’s signed rank test. Results: Azoles were the most commonly prescribed antifungals. Clinical status of patients was independent of the oral antifungal drug received (p &gt; 0.05). A statistically significant difference in clinical status between compliant and non-compliant patients was seen (p &lt; 0.05). A statistically significant increase in serum ALT levels was seen (p &lt; 0.05) however, it was not clinically significant. 55.52% of drugs were unavailable in the hospital formulary. The average expenses per prescription was approximately INR 1123.55. Itraconazole was the most expensive treatment regimen followed by terbinafine and fluconazole. Conclusions: There exists a non-uniformity in the management of dermatophytoses due to lack of adequate guidance and nonavailability of drugs and clinical cure of patients depends upon compliance to therapy.

Lipid emulsions for parenterally fed term and late preterm infants.

Lipid emulsions for parenterally fed term and late preterm infants.

Inhibition of CYP2E1 With Propylene Glycol Does Not Protect Against Hepatocellular Injury in Human Acetaminophen Daily-Dosing Model.

Acetaminophen (APAP)-induced liver injury is initiated by metabolism of APAP by the cytochrome P-450 (CYP) system, primarily CYP2E1. We previously demonstrated CYP inhibition following administration of a liquid APAP formulation containing propylene glycol, a CYP2E1 inhibitor, and other excipients. This study was undertaken to determine if propylene glycol specifically inhibits production of CYP-derived metabolites and if propylene glycol reduces the rise in alanine aminotransferase (ALT) seen following prolonged APAP dosing. Human subjects were randomized to receive 4 g of APAP daily in one arm of the study or 4 g of APAP with 5 mL of 99% propylene glycol in the other arm, both for 14 days. After a washout period of at least 14days, subjects were crossed over between arms. Outcomes were rise of ALT greater than 2 times baseline (responders) and proportion of randomly sampled CYP-derived metabolites relative to total metabolites produced. There was no difference in percentage of responders between treatment groups: 6 of 21 in the APAP group (29%) compared with 8 of 20 in the APAP + propylene glycol group (40%); chi-square, P=.59. For all subjects, the mean percentage of CYP-derived metabolites produced was 5.8% (APAP) versus 4.3% (APAP + propylene glycol); P=.018. This effect was solely attributable to the responders: the mean percentage of CYP metabolites of responders was 7.7% (APAP) versus 4.6% (APAP+propylene glycol), P=.050, whereas there was no difference for the nonresponders. Five subjects were responders in both arms (2% probability of random occurrence). Our data indicates that propylene glycol inhibits CYP2E1 metabolism of APAP in some subjects but does not effect hepatocellular indury at the dose given.