Gamma-glutamyl Transferase Levels Research Articles

Gender Differences in Liver Steatosis and Fibrosis in Overweight and Obese Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease before and after 8 Weeks of Very Low-Calorie Ketogenic Diet

Obesity and metabolic syndrome are linked to steatotic liver disease (SLD), the most common form of chronic liver disease. Lifestyle modifications and dieting are strategies that can prevent metabolic dysfunction-associated steatotic liver disease (MASLD). The very low-calorie ketogenic diet (VLCKD) is a helpful treatment for MASLD and has been recommended for people affected by obesity; we evaluated the effect of gender on steatosis and fibrosis in a cohort of 112 overweight or obese patients undergoing an eight-week treatment with a VLCKD. Differences between the genders in terms of anthropometric measures, body composition, and metabolic indicators were examined before, during, and after the nutritional intervention. At baseline, there were significant differences between men and women in terms of anthropometric parameters, blood pressure, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), fasting insulin, hepatic markers, and lipid profile. Men had considerably higher levels of liver steatosis (measured by CAP) and liver stiffness (measured by E) under basal conditions than women. After the VLCKD, there were reductions in both genders of controlled attenuation parameter (CAP), body weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, insulin resistance, fat mass (FM), free fat mass (FFM), and fasting blood glucose, insulin, glycated hemoglobin (HbA1c), triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, alanine transaminase (ALT), gamma-glutamyl transferase (γGT), and uric acid levels. Only in men, liver stiffness, aspartate aminotransferase (AST), creatinine, and C-reactive protein (CRP) levels significantly decreased. Moreover, men had significantly greater levels of liver steatosis: the male gender featured an increase of 23.96 points of the Fibroscan CAP. Men exhibited higher levels of steatosis and fibrosis than women, and these differences persist despite VLCKD. These gender-specific variations in steatosis and fibrosis levels could be caused by hormonal and metabolic factors, suggesting that different therapeutic strategies might be required depending on the gender.

Preclinical Testing of Chronic ICA-1S Exposure: A Potent Protein Kinase C-ι Inhibitor as a Potential Carcinoma Therapeutic

Protein kinase C-iota (PKC-ι) is an oncogene overexpressed in many cancer cells including prostate, breast, ovarian, melanoma, and glioma cells. Previous in vitro studies have shown that 5-amino-1-((1R,2S,3R,4R)-2-3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-1H-imidazole-4-carboxamide (ICA-1S), a PKC-ι-specific inhibitor, has low toxicity in both acute and sub-acute mouse model toxicological testing and is an effective therapeutic against several cancer cell lines showing significant reductions in tumor growth when treating athymic nude mice with xenografted carcinoma cell lines. To further assess ICA-1S as a possible therapeutic agent, chronic mouse model toxicological testing was performed in vivo to provide inferences concerning the long-term effects and possible health hazards from repeated exposure over a substantial part of the animal’s lifespan. Subjects survived well after 30, 60, and 90 days of doses ranging from 50 mg/kg to 100 mg/kg. Heart, liver, kidney, and brain tissues were then analyzed for accumulations of ICA-1S including the measured assessment of aspartate transaminase (AST), alkaline phosphatase (ALK-P), gamma-glutamyl transferase (GGT), troponin, and C-reactive protein (CRP) serum levels to assess organ function. Predictive in vitro/in silico methods were used to predict compound-induced direct hepatocyte toxicity or renal proximal tubular cell (PTC) toxicity in humans based on the high-content imaging (HCI) of compound-treated cells in combination with phenotypic profiling. In conclusion, ICA-1S shows low toxicity in both acute and chronic toxicology studies, and shows promise as a potential therapeutic.

Psoriasis Area and Severity Index and its Correlation with Liver Function Test

Objective: To determine Psoriasis Area and Severity Index score and its association with LFT values in patients of psoriasis. Methodology: This cross-sectional study, was done on patients visiting the skin OPD of LUMHS Jamshoro/Hyderabad. Diagnosed patients of Psoriasis, aged between 18 and 50 years and both genders were included. A 5cc blood sample was collected from each individual to evaluate the LFT. Psoriasis Area and Severity Index (PASI) scores was defined based on the percentage of body surface area affected by psoriasis lesion. All the information was entered and analyzed using SPSS version 26. Results: The mean age of the patients was 44.81±11.10 years. Out of the total 102 patients, 74.5% were male patients and 25.5% were female. The mean duration of psoriasis was 6.46 ± 4.49 years. Out of all 32.4% had mild psoriasis (PASI < 7), 40.2% had moderate psoriasis (PASI 8-12), and 27.5% had severe psoriasis (PASI > 12). Regarding LFT values, 73.5% had elevated alanine transaminase (ALT), 32.4% had elevated aspartate transaminase (AST), 70.6% had elevated alkaline phosphatase (ALP), 68.6% had elevated bilirubin, and 67.6% had elevated gamma-glutamyl transferase (GGT). AST and GGT levels rise significantly linked to PASI (p- <0.05). Conversely, for ALP and Bilirubin levels, there is no significant difference across severity of PASI (p- >0.05). Conclusion: Patients with severe psoriasis exhibit a predisposition to hepatic dysfunction. Study observed abnormalities in liver function tests (LFT) among psoriatic patients, suggesting a potential link to liver disease development.

Risk and timing of isotretinoin-related laboratory disturbances: a population-based study.

Uncertainty surrounds the optimal routine laboratory monitoring in acne patients treated with isotretinoin. Our aim was to evaluate the risk of mild and severe laboratory abnormalities in patients with acne starting isotretinoin versus oral antibiotic treatment. A global population-based retrospective cohort study assigned two groups of patients with acne-prescribed isotretinoin (n = 79,012) and oral antibiotics (n = 79,012). Comprehensive propensity-score matching was conducted. Compared to acne patients treated with oral antibiotics, those under isotretinoin demonstrated an increased risk of grade ≥3 hypertriglyceridemia (hazard ratio [HR], 7.85; 95% confidence interval [CI], 5.58-11.05; P < 0.001) and grade ≥3 elevated aspartate transaminase (AST) levels (HR, 1.45; 95% CI, 1.13-1.85; P = 0.003) within the initial 3 months of treatment. The absolute risk of these abnormalities among isotretinoin initiators was 0.4% and 0.2%, respectively. The risk difference of these findings was clinically marginal: 3 and 1 additional cases per 1,000 patients starting isotretinoin, respectively. There was no significant risk of grade ≥3 impairment in cholesterol, alanine transaminase, gamma-glutamyl transferase, or creatinine levels under isotretinoin. Most laboratory abnormalities were documented 1-3 months after drug initiation in time-stratified analysis. Isotretinoin is associated with a clinically marginal increased risk of severe hypertriglyceridemia and hypertransaminasemia. Routine blood testing should be performed 1-3 months after commencing therapy.

Topiramate Versus Naltrexone for Alcohol Use Disorder: A Genotype-Stratified Double-Blind Randomized Controlled Trial.

There have been no well-controlled and well-powered comparative trials of topiramate with other pharmacotherapies for alcohol use disorder (AUD), such as naltrexone. Moreover, the literature is mixed on the effects of two polymorphisms-rs2832407 (in GRIK1) and rs1799971 (in OPRM1)-on response to topiramate and naltrexone, respectively. The authors sought to examine the comparative effectiveness of topiramate and naltrexone in improving outcomes in AUD and to examine the role of the rs2832407 and rs1799971 polymorphisms, respectively, on response to these medications. In a 12-week, double-blind, placebo-controlled, randomized, multisite, genotype-stratified (rs2832407 and rs1799971) clinical trial comparing topiramate and naltrexone in treating AUD, 147 patients with AUD were randomly assigned to treatment with topiramate or naltrexone, stratified by genotype (rs2832407*CC and *AC/AA genotypes and rs1799971*AA and *AG/GG genotypes). The predefined primary outcome was number of heavy drinking days per week. Predefined secondary outcomes included standard drinks per drinking day per week, body mass index (BMI), craving, markers of liver injury, mood, and adverse events. For the number of heavy drinking days per week, there was a near-significant time-by-treatment interaction. For the number of standard drinks per drinking day per week, there was a significant time-by-treatment interaction, which favored topiramate. There were significant time-by-treatment effects, with greater reductions observed with topiramate than naltrexone for BMI, craving, and gamma-glutamyltransferase level. Withdrawal due to side effects occurred in 8% and 5% of the topiramate and naltrexone groups, respectively. Neither polymorphism showed an effect on treatment response. Topiramate is at least as effective and safe as the first-line medication, naltrexone, in reducing heavy alcohol consumption, and superior in reducing some clinical outcomes. Neither rs2832407 nor rs1799971 had effects on topiramate and naltrexone treatments, respectively.

A genome-first approach to variants in MLXIPL and their association with hepatic steatosis and plasma lipids.

Common variants of the max-like protein X (MLX)-interacting protein-like (MLXIPL) gene, encoding the transcription factor carbohydrate-responsive element-binding protein, have been shown to be associated with plasma triglyceride levels. However, the role of these variants in steatotic liver disease (SLD) is unclear. We used a genome-first approach to analyze a variety of metabolic phenotypes and clinical outcomes associated with a common missense variant in MLXIPL, Gln241His, in 2 large biobanks: the UK Biobank and the Penn Medicine Biobank. Carriers of MLXIPL Gln241His were associated with significantly lower serum levels of triglycerides, apolipoprotein-B, gamma-glutamyl transferase, and alkaline phosphatase. Additionally, MLXIPL Gln241His carriers were associated with significantly higher serum levels of HDL cholesterol and alanine aminotransferase. Carriers homozygous for MLXIPL Gln241His showed a higher risk of SLD in 2 unrelated cohorts. Carriers of MLXIPL Gln241His were especially more likely to be diagnosed with SLD if they were female, obese, and/or also carried the PNPLA3 I148M variant. Furthermore, the heterozygous carriage of MLXIPL Gln241His was associated with significantly higher all-cause, liver-related, and cardiovascular mortality rates. Nuclear magnetic resonance metabolomics data indicated that carriage of MLXIPL Gln241His was significantly associated with lower serum levels of VLDL and increased serum levels of HDL cholesterol. Analyses of the MLXIPL Gln241His polymorphism showed a significant association with a higher risk of SLD diagnosis and elevated serum alanine aminotransferase as well as significantly lower serum triglycerides and apolipoprotein-B levels. MLXIPL might, therefore, be a potential pharmacological target for the treatment of SLD and hyperlipidemia, notably for patients at risk. More mechanistic studies are needed to better understand the role of MLXIPL Gln241His on lipid metabolism and steatosis development.

Depletion of hepatic glutathione and adenosine by glucocorticoid exposure in Wistar rats is pregnancy-independent

Liver diseases have gained increasing attention due to their substantial impact on health, independently as well as in association with cardio-metabolic disorders. Studies have suggested that glutathione and adenosine assist in providing protection against oxidative stress and inflammation while glucocorticoid (GC) therapy has been associated with chronic inflammatory disorders, even in pregnancy. The implications of Glucocorticoid exposure on maternal health and fetal growth is a concern, however, the possible role of glutathione and adenosine has not been thoroughly investigated. The study therefore hypothesize that exposure to glucocorticoids leads to depletion of hepatic glutathione and adenosine levels, contributing to oxidative stress and tissue injury. Additionally, we aim to investigate whether the effects of glucocorticoids on hepatic health are pregnancy dependent in female rats. Twelve Pregnant and twelve age-matched non-pregnant rats were used for this study; an exogenous administration of glucocorticoid (Dex: 0.2 mg/kg) or vehicle (po) was administered to six pregnant and six non-pregnant rats from gestational day 14 to 19 or for a period of 6 days respectively. Data obtained showed that GC exposure led to a decrease in hepatic glucose-6-phosphate dehydrogenase, glutathione peroxidase, GSH/GSSG ratio and adenosine content in both pregnant and non-pregnant rats. In addition, increased activities of adenosine deaminase and xanthine oxidase, along with increased production of uric acid and increased levels of lactate dehydrogenase, aspartate aminotransferase, alanine transferase, alkaline phosphatase and gamma-glutamyl transferase were observed. In summary, the study indicates that GC-induced liver damage is underlined by depleted hepatic adenosine and glutathione levels as well as elevated markers of tissue inflammation and/or injury. Furthermore, the findings suggest that the effects of GC exposure on hepatic health are pregnancy independent.

Gamma-glutamyl transferase and the risk of all-cause and disease-specific mortality in patients with diabetes: A nationwide cohort study.

There exists a paucity of data regarding whether gamma-glutamyl transferase is associated with disease-specific mortality in patients with type 2 diabetes mellitus. This study aimed to investigate the association of serum gamma-glutamyl transferase levels with all-cause and disease-specific mortality in patients with diabetes mellitus using a Korean nationwide health-screening database. A total of 9 687 066 patients without viral hepatitis or liver cirrhosis who underwent health examination in 2009 were included. These patients were divided into four groups according to sex-specific quartiles of serum gamma-glutamyl transferase levels. During a median follow-up period of 8.1 years, 222 242 deaths were identified. The all-cause mortality rate increased as the serum gamma-glutamyl transferase levels became higher (highest quartile vs lowest quartile: hazard ratio [HR], 1.57; 95% confidence interval [CI], 1.55-1.59; p for trend <.001). Similar trends were observed for cardiovascular disease (HR, 1.57; 95% CI, 1.53-1.62), ischemic heart disease (HR, 1.40; 95% CI, 1.33-1.48), and stroke (HR, 1.72; 95% CI, 1.60-1.85) in the highest quartile, as compared with the lowest quartile (p for trend <.001). As the gamma-glutamyl transferase quartiles became higher, mortality rates related to cancer (HR, 1.56; 95% CI, 1.52-1.60), liver disease (HR, 9.42; 95% CI, 8.81-10.07), respiratory disease (HR, 1.55; 95% CI, 1.49-1.62), and infectious disease (HR, 1.73; 95% CI, 1.59-1.87) also increased in the highest quartile, compared with the lowest quartile (p for trend <.001). Serum gamma-glutamyl transferase levels may be useful for the risk assessment of all-cause and disease-specific mortality among patients with type 2 diabetes mellitus.

Clinico-haematobiochemical and cardiac alterations in Trypanosoma evansi infected buffaloes of Andhra Pradesh, India.

The present research aimed to document the incidence, clinical signs, haematological, and serum biochemical alterations, as well as electrocardiography and echocardiography findings in 62 buffaloes (selected from a total of 240) infected with Trypanosoma evansi. The study spanned one year, from January 2022 to December 2022. Morphological identification of Trypanosoma evansi was done by the presence of a centrally positioned nucleus with a small sub-terminal kinetoplast at the posterior position through microscopic examination of Giemsa stained peripheral blood smears. The incidence of trypanosomosis were determined to be 26% (62/240) using stained blood smear examination and 41% (98/240) through polymerase chain reaction assay. Clinical signs exhibited by buffaloes with trypanosomosis included the lack of rumination (94%; 58/62), anorexia (90%; 56/62), emaciation (87%; 54/62), loss of milk yield (84%; 52/62), ocular discharges (82%; 51/62), depressed demeanour (81%; 50/62), sunken eye balls (61%; 38/62), fever (60%; 37/62), scleral congestion (56%; 35/62) and intermittent fever (42%; 26/62). Cardiovascular clinical findings in affected buffaloes included tachycardia (44%; 27/62), cardiac arrhythmia (24%; 15/62), cardiac murmurs (19%; 12/62) and muffled heart sounds (18%; 11/62). In the present study, buffaloes with trypanosomosis exhibited significant reduction in haemoglobin (p = 0.008), packed cell volume (p = 0.004), total erythrocyte count (p = 0.003), mean corpuscular volume (p = 0.042), total leucocyte count (p = 0.048) and absolute neutrophil count (p = 0.012); a significant increase in absolute eosinophil count (p = 0.011) and absolute monocyte count (p = 0.008) compared to the apparently healthy buffaloes. Additionally significant decrease in albumin (p = 0.001), A/G ratio (p = 0.007), calcium (p = 0.008), glucose (p = 0.007), phosphorous (p = 0.048), sodium (p = 0.008), potassium (p = 0.041) and chloride (p = 0.046) were observed in buffaloes with trypanosomosis compared to healthy ones. Buffaloes with trypanosomosis also showed significant increase in globulin (p = 0.004), aspartate aminotransferase (p = 0.008), bilirubin (p = 0.034), blood urea nitrogen (p = 0.071), creatinine (p = 0.029), cholesterol (p = 0.046), lactate dehydrogenase (p = 0.009), gamma-glutamyl transferase (p = 0.004) and creatine kinase-myoglobin binding levels (p = 0.005). Electrocardiography explorations in buffaloes with trypanosomosis revealed sinus tachycardia, low voltage QRS complex, ST segment elevation, wide QRS complex, sinus arrhythmia, sinus bradycardia, wandering pace maker, first degree atrio ventricular block, biphasic T wave and tall T wave. Echocardiography examination unveiled cardiac chamber dilatation, ventricular wall thickening and indications of pericarditis/cardiac tamponade. Necropsy was carried on the dead buffaloes during the study period disclosed severely congested blood vessels on epicardial surface, endocardial haemorrhages, and presence of pericardial fluid. Histopathological examination of the heart revealed hyaline degeneration, haemorrhages in the cardiac muscles and varying degrees of degenerative changes. Additionally, the pericardium displayed increased thickness due to presence of more elastic fibres, fibroblast cells in the myocardium, discontinuity of muscle layers, vascular congestion, perivascular mono nuclear cell infiltration and augmented thickness of the endocardium with fibroblast cell proliferation. The study's conclusion highlights cardiac alterations as secondary complications in buffaloes infected with Trypanosoma evansi. Further investigations are recommended to elucidate therapeutic modifications and refine the treatment paradigm.

Pancreatobiliary reflux increases macrophage-secreted IL-8 and activates the PI3K/NFκB pathway to promote cholangiocarcinoma progression

BackgroundPersistent pancreaticobiliary reflux (PBR) is associated with a high risk of biliary malignancy. This study aimed to evaluate the proportion of PBR in biliary tract diseases and mechanisms by which PBR promoted cholangiocarcinoma progression. MethodsOverall 227 consecutive patients with primary biliary tract disease participated in this study. The amylase levels in the collected bile were analyzed. The mechanisms underlying the effect of high-amylase bile on bile duct epithelial and cholangiocarcinoma cells progression were analyzed. The source of interleukin-8 (IL-8) and its effects on the biological functions of cholangiocarcinoma cells were investigated. ResultsThe bile amylase levels in 148 of 227 patients were higher than the upper serum amylase limit of 135 IU/L. PBR was significantly correlated with sex, pyrexia, and serum gamma-glutamyl transferase (GGT) levels in the patient cohort. High-amylase bile-induced DNA damage and genetic differences in the transcript levels of the gallbladder mucosa and facilitated the proliferation and migration of bile duct cancer cells (HUCCT1 and QBC939 cells). The concentration of many cytokines increased in high-amylase bile. IL-8 is secreted primarily by macrophages via the mitogen-activated protein kinase pathway and partially by bile duct epithelial cells. IL-8 promotes the progression of HUCCT1 and QBC939 cells by regulating the expression of epithelial-mesenchymal transition-associated proteins and activating the phosphatidylinositol 3-kinase/nuclear factor kappa-B pathway. ConclusionsPBR is one of the primary causes of biliary disease. IL-8 secreted by macrophages or bile duct epithelial cells stimulated by high-amylase bile promotes cholangiocarcinoma progression.

Various Patterns of the Derangement of Liver Function Tests in End-Stage Renal Disease Patients on Maintenance Hemodialysis-A Single Centered Study from Pakistan

Background: Chronic kidney disease (CKD) patients on maintenance hemodialysis often present with various comorbidities, among which liver dysfunction is not uncommon. The prevalence of hepatitis B and C among this population suggests a multifaceted interaction between liver health and renal impairment. Studies have indicated that serum aminotransferase levels are inversely related to the severity of CKD and may be affected by hemodialysis. Objective: This study aimed to delineate the patterns and etiologies of liver function test derangements in an end-stage renal disease (ESRD) cohort on maintenance hemodialysis, assessing the association between dialysis duration and liver enzyme levels. Methods: In this cross-sectional observational study, 91 ESRD patients undergoing hemodialysis at a single center were evaluated. Liver function patterns were classified as hepatocellular, cholestatic, or mixed based on serum levels of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALKP), and gamma-glutamyl transferase (GGT). Statistical analysis was performed using SPSS version 25, with a significant p-value set at ≤ 0.05. Results: The average age of patients was 44 ± 15 years. The majority had been on dialysis for one (41.8%) or two years (33%). Hepatitis C (20.9%) was the predominant cause of viral hepatitis, followed by Hepatitis B (13.2%). Sepsis was identified as a major contributor to liver enzyme derangement (58.2%). The most common pattern of deranged liver enzymes was mixed (49.5%), followed by cholestatic (27.5%) and hepatocellular (23%). Elevated transaminases were noted, with AST at 227.8 ± 264.1 IU/mL and ALT at 237.1 ± 281.8 IU/mL. Conclusion: In the studied ESRD population, sepsis was the leading cause of liver dysfunction, with a higher incidence of mixed liver enzyme pattern derangements. The elevated aminotransferase levels contrast with previous studies, suggesting the need for enhanced infection control and consistent monitoring of liver health in the hemodialysis setting.

Evaluation of Hematological and Biochemical Effects of Kabuuti Herbal Cough Syrup: A Sub-acute Study in Wistar Rats

Herbal medicines, including Kabuuti cough syrup, have gained popularity in treating various ailments, yet their safety and efficacy require scientific scrutiny. This study aimed to evaluate the hematological and biochemical effects of Kabuuti herbal cough syrup after 28 days of oral administration in Wistar rats. The herbal extracts, containing secondary metabolites like terpenes, alkaloids, steroids, and phenols, were administered at different doses to rats, with distilled water as a control. Hematological and biochemical parameters were assessed, showing no statistically significant changes in most parameters. However, there were decreases in mean corpuscular volume (MCV) levels and lymphocyte percentage and increases in hemoglobin (HB) levels and gamma glutamyl transferase (GGT) levels observed in certain dosage groups. Despite these variations, the overall findings suggest that Kabuuti herbal cough syrup is safe for liver and kidney function in the short term, with no significant adverse effects observed. Keywords: Kabuuti Cough Herbal Preparation; Haematological Effects; Biochemical Effects; Oral Administration; Wistar Rats.

Adipokine (adiponectin-rs1501299) Gene Variant and Patient Characteristics in Relation to Metabolic-associated Fatty Liver Disease

BackgroundSeveral genetic and metabolic variables, most notably the variation in the adipokine gene rs1501298, have been linked to metabolic-associated fatty liver disease etiopathogenesis (MAFLD). Liver biopsy, the gold standard for diagnosing MAFLD, is an invasive procedure; therefore, alternative diagnostic methods are required. Consequently, the integration of these metabolic variables with some of the patients’ characteristics may facilitate the development of non-invasive diagnostic methods that aid in the early detection of MAFLD, identification of at-risk individuals, and planning of management strategies. MethodsThis study included 224 Egyptians (107 healthy individuals and 117 MAFLD patients). Age, sex, BMI, clinical and laboratory characteristics, and rs1501299 adipokine gene polymorphisms were examined. The Rs1501299 variant, insulin resistance, hypertension, obesity, blood pressure, lipid profile, hemoglobin A1C level, and hepatic fibrosis predictors were evaluated for MAFLD risk. The feasibility and effectiveness of developing non-invasive MAFLD diagnostic models will be investigated. ResultsThe +276G/T (rs1501299) polymorphism (GG vs GT/TT) was linked with MAFLD (OR: 0.43, CI: 0.26-0.69, p=0.002). The GG variants had lower MAFLD rates than those of the GT and TT variants. In addition to altered lipid profiles, patients with MAFLD showed increased gamma-glutamyl transferase levels (GGT: 56 IU/L vs. 36 IU/L). Genetic diversity also affects the accuracy of hepatic fibrosis and steatosis prediction. Hepatic fibrosis and steatosis predictors had ROC AUCs of 0.529%, 0.846%, and 0.700–0.825%, respectively. We examined a diagnostic model based on these variables, and demonstrated its effectiveness. ConclusionThe Adipokine variant rs1501299 increased the risk of MAFLD. Identifying and genotyping this variation and other metabolic variables allows for a non-invasive diagnostic model for early MAFLD diagnosis and identification of those at risk. This study illuminates the prevention and management of MAFLD. Further research with more participants is needed to verify these models and to prove their MAFLD diagnostic efficacy.

Abstract CT142: Phase 1 study of BPI-23314, a novel BET inhibitor and degrader, in advanced myeloid leukemia (AML)

Abstract Background: The novel small-molecule inhibitor and degrader, BPI-23314, targeting of the bromodomain and extra-terminal domain (BET) family proteins, BPI-23314, has been showndemonstrated promising preclinical efficacy in hematologic malignancies. This Phase 1 study aims to evaluate the safety, pharmacokinetics, and preliminary efficacy of BPI-23314 monotherapy in patients with relapsed or refractory acute myeloid leukemia (R/R AML). Methods: This ongoing phase 1 study of BPI-23314 enrolled adult patients with R/R AML. Dose escalation was conducted using a standard 3+3 design, followed by additional expansion cohorts to further assess safety and preliminary efficacy. BPI-23314 tablets were administered orally once daily (QD) or twice daily (BID) in consecutive 21-day cycles. The key endpoints included determining the recommended Phase 2 dose (RP2D), safety, pharmacokinetics, and preliminary efficacy. Results: As of July 31, 2022, a total of 22 patients diagnosed with R/R AML were treated with BPI-23314 at seven different dose levels, ranging from 5 to 60 mg QD or 40 to 50 mg BID. The median age of the patients was 48 years (range: 19-68 years), and the median treatment duration was 6 weeks (range: 2-9 weeks). The median number of prior therapy lines was 3 (range: 1-4), with 15 (68.2%) being refractory to last line of therapy. Due to the high incidence of grade≥3 anemia, thrombocytopenia, and neutropenia among the patients at baseline, most treatment-emergent adverse events (TEAE) of hematologic toxicities were mainly correlated with disease progression. Only one patient experienced grade 3 treatment-related adverse events (TRAE) comprising anemia (4.5%) and neutropenia (4.5%). Non-hematologic TRAEs were predominantly of grade 1-2. The most common TRAEs (≥10%) were gastrointestinal reactions (10/22, 45.5%), hypertriglyceridemia (6/22, 27.3%), hyperbilirubinemia (4/22, 18.2%), elevated alanine aminotransferase levels (3/22, 13.6%), and increased gamma-glutamyl transferase levels (3/22, 13.6%). Gastrointestinal reactions characterized by nausea and/or diarrhea were the most commonly reported toxicities. The most common TEAEs associated with disease progression were infection and bleeding. No dose-limiting toxicity or treatment-related deaths were reported during the study period, and the maximum tolerated dose was not reached. Among the evaluable responses in all dose levels for R/R AML patients (n=21), one patient achieved complete response (CR) at a dosage of 40 mg BID while three patients maintained stable disease (SD) across various dosages, including QD at 60 mg and BID at both 40 mg and 50 mg. Furthermore, BPI-23314 demonstrated moderate elimination kinetics, with a plasma half-life ranging from 8.6 to 23.3 hours, while exhibiting dose-proportional exposure. Conclusion: BPI-23314 monotherapy exhibited preliminary clinical efficacy with manageable adverse events in patients with R/R AML. The study is ongoing. The satisfactory pharmacokinetic attribute and outstanding safety profile of BPI-23314 provide compelling rationales for further exploration of its therapeutic potential. Citation Format: Mingyuan Sun, Xiangyu Jin, Jing Guo, Xiaoyun Liu, Yan Xu, Hong Lan, Jiabing Wang, Jiangnan Zhen, Jing Yang, Lieming Ding, Junyuan Qi. Phase 1 study of BPI-23314, a novel BET inhibitor and degrader, in advanced myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT142.

Gut Bifidobacterium longum is Associated with Better Native Liver Survival in Patients with Biliary Atresia

Background & AimsThe gut microbiome plays an important role in liver diseases, but its specific impact on biliary atresia (BA) remains to be explored. We aimed to investigate the microbiota signature in the early life of patients with BA and to analyze its influence on long-term outcomes. MethodsFecal samples (n=42) were collected from infants with BA before and after Kasai portoenterostomy (KPE). The stool microbiota was analyzed using 16S rRNA next-generation sequencing (NGS) and compared with that of age-matched healthy controls (HCs). Shotgun metagenomic sequencing analysis was employed to confirm the bacterial composition in 10 fecal samples before KPE. The correlation of the microbiome signature with liver function and long-term outcomes was assessed. ResultsIn the 16S rRNA NGS fecal microbial analysis, the alpha and beta diversity analyses revealed significant differences between HCs and patients with BA before and after KPE. The difference in microbial composition analyzed by linear discriminant analysis and random forest classification revealed that the abundance of Bifidobacterium longum (B. longum) was significantly lower in patients before and after KPE than in HCs. The abundance of B. longum was negatively correlated with the gamma-glutamyl transferase level after KPE (P<0.05). Patients with early detectable B. longum had significantly lower total and direct bilirubin 3 months after KPE (P<0.005) and had a significantly lower liver transplantation rate (hazard ratio: 0.16, 95% CI: 0.03-0.83, P=0.029). Shotgun metagenomic sequencing also revealed that BA patients with detectable B. longum had reduced total and direct bilirubin after KPE. ConclusionThe gut microbiome of patients with BA differed from that of HCs, with a notable abundance of B. longum in early infancy correlating with better long-term outcomes. Impact and implicationsB. longum is a beneficial bacterium commonly found in the human gut. It has been studied for its potential impacts on various health conditions. In patients with BA, we found that a greater abundance of B. longum in the fecal microbiome is associated with improved clinical outcomes. This suggests that early colonization and increasing B. longum levels in the gut could be a therapeutic strategy to improve the prognosis of patients with BA.

Changes in liver health biomarkers following consumption of energy restricted diets containing almonds compared with carbohydrate-rich snack foods for 9 months

Energy restricted diets improve liver function(1) and habitual nut consumption has been associated with a lower prevalence of fatty liver(2). This study examined the effect of incorporating almonds in an energy restricted diet on liver health biomarkers. One Hundred and forty adults (42M:98F, 47.5 ± 10.8 years, BMI 30.7 ± 2.3 kg/m2) enrolled in a 9-month (9M) dietary intervention comprising 3 months (3M) weight loss (30% energy restriction) followed by 6 months (6M) of weight maintenance. Participants were randomly assigned to consume almonds (n = 68, AED) or isocaloric carbohydrate-rich snacks (n = 72, CRD) which provided 15% of total daily energy. At baseline (BL), 3M and 9M, fatty liver index (FLI) scores (0-100)(3) were calculated using body mass index (BMI), waist circumference (WC), fasting serum gamma-glutamyl transferase (GGT) and triglyceride (TAG) levels, and other liver health biomarkers were assessed by ultrasound (volume, visual appearance and elastography (a marker of stiffness due to fibrosis)). Intention to treat analyses were conducted using mixed effects modelling (fixed effects group and time, with participants as the random effect). Significant reductions from BL occurred over time (all p&lt;0.001 for 3M and 9M) with no difference between groups (AED vs CRD, P&gt;0.05) in BMI (3M: −2.44 ± 0.20 vs −2.32 ± 0.20, 9M: −2.83 ± 0.19 vs −2.81 ± 0.19 kg/m2), WC (3M: −8.04 ± 0.79 vs −7.00 ± 0.81, 9M: −8.72 ± 0.83 vs −9.14 ± 0.81 cm), TAG (3M: −0.24± 0.08 vs −0.22 ± 0.09, 9M: −0.37 ± 0.09 vs −0.21 ± 0.09 mmol/L), FLI score (3M: −23.8 ± 2.0 vs −17.6 ± 2.1, 9M: −23.8 ± 2.0 vs −17.6 ± 2.1), and liver volume (3M: −134.56 ± 38.30 vs −100.96 ± 37.25, 9M: −113.68 ± 37.42 vs −110.64 ± 35.47cm3). Significantly greater reductions occurred for AED compared to CRD at 3M and 9M in GGT (p = 0.003) (3M: −9.68 ± 1.93 vs −0.01 ± 2.00, 9M: −7.75 ± 2.06 vs −2.78 ± 2.15 IU/L) and liver visual assessment scores (p = 0.03) (3M: −0.58 ± 0.24 vs −0.45 ± 0.23, 9M: −1.33 ± 0.23 vs −0.50 ± 0.22). There were no significant changes in liver elastography over time or between groups. Energy restriction improved body composition and reduced the extent of fatty liver and liver size but did not change liver stiffness. The inclusion of almonds in an energy restricted diet demonstrated additional benefits to some liver health biomarkers providing support for almonds being incorporated into lifestyle interventions to improve liver function.

Exploratory Study on the Relationship Between Age, Reproductive Stage, Body Condition Score, and Liver Biochemical Profiles in Rembi Breed Ewes

Background: The Rembi sheep breed is renowned for its exceptional meat quality and significant economic profit. Nevertheless, there is a gap in research on the hepatic parameters of this breed in Algeria despite the considerable value of the liver in the Algerian population’s diet. Objectives: The research aimed to determine the impact of physiological factors (age, physiological stage, and body condition score) on biochemical sheep liver parameters. Methods: Sixty clinically healthy female Rembi breed sheep, aged between 3 months and 7 years, raised at the Technical Institute of Livestock (ITELV) Ksar Chellala Farm in Tiaret Province, Algeria, were selected for biochemical analysis and assessing aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), total bilirubin (TBIL), direct bilirubin (DBIL), albumin (ALB), and total protein (TP). Results: The concentrations of AST, ALP, and GGT increased significantly (P≤0.001) in young sheep, while ALT and TP levels decreased (P≤0.05). However, a high level of GGT (P&lt;0.001) was also observed in lactating ewes, and during pregnancy, females have a low level of ALP (P&lt;0.001). Furthermore, the body condition score does not affect any of the measurements. Conclusion: Considering the animal’s age and physiological stage is critical before interpreting the results.

The Importance of Evaluating Sudomotor Function in the Diagnosis of Cardiac Autonomic Neuropathy.

Cardiac autonomic neuropathy (CAN) is a disorder affecting the autonomic nerves that regulate the cardiovascular system, leading to irregular heart rate and blood pressure control. It is commonly associated with diabetes mellitus but can also result from other conditions such as autoimmune disorders, chronic kidney disease, alcohol abuse, and certain medications. Screening for CAN is essential, particularly in individuals with poor glycemic control, cardiovascular risk factors, or complications. Early identification of CAN is vital for timely intervention to prevent or manage cardiovascular complications effectively. Regular screening helps detect CAN before symptoms emerge, enabling early intervention to slow or halt its progression. This study examined the relationship between sudomotor function and cardiovascular reflex tests. This was a cross-sectional study conducted between June 2019 and June 2020. The study included 271 subjects aged 18 years and above who provided informed consent, were diagnosed with type 2 diabetes mellitus (T2DM), and were overweight or obese. Exclusion criteria encompassed patients with other types of diabetes, pregnant women, those with recent neoplasm diagnoses, stroke sequelae, history of myocardial infarction, or pelvic limb amputations. The assessment of cardiac autonomic neuropathy involved conducting an electrocardiogram and evaluating the QTc interval in the morning before taking medication. Additionally, cardiovascular reflex tests (CART) were conducted, including assessments of heart rate variability during deep breathing, the Valsalva maneuver, and changes in orthostatic position. Simultaneously, the diagnosis of CAN was assessed by performing a sweat test using a Sudoscan assessment (Impeto Medical, Moulineaux, France). Results: More than half of the participants (52%, n=143) were female. Significant differences in statistical measures were noted between females and males regarding age, systolic blood pressure, fasting blood glucose, A1c level, total cholesterol, triglycerides, gamma-glutamyl transferase, and bilirubin levels. Within the CAN-diagnosed group (CAN+), 40.92% were classified as mild cases (n=90), 47.27% as moderate cases (n=104), and 11.81% as severe cases (n=26). Among the CAN+ group, 54% (n=119) were women. Electrochemical skin conductance was lower in the CAN+ group than the CAN- group in hands (67.34±15.51 μS versus 72.38±12.12 μS, p=0.008) and feet (73.37±13.38 μS versus 82.84 ±10.29 μS, p<0.001). The Sudoscan-CAN score significantly correlated with Ewing scores (r= 0.522, p<0.001). In multiple linear regression analysis, the Sudoscan-CAN score remained significantly associated with age, high BMI, long-standing diabetes, and Ewing score. Sudoscan demonstrates potential in identifying patients with an increased risk of CAN. Its integration into clinical practice can improve patient outcomes through early detection, risk stratification, and personalized treatment approaches. Its non-invasive, portable, and user-friendly features render it suitable for utilization in outreach programs or resource-constrained settings as part of screening efforts designed to pinpoint high-risk individuals for additional assessment.

Subnormal Serum Liver Enzyme Levels: A Review of Pathophysiology and Clinical Significance.

Subnormal levels of liver enzymes, below the lower limit of normal on local laboratory reports, can be useful diagnostically. For instance, subnormal levels of aminotransferases can be observed in vitamin B6 deficiency and chronic kidney disease. Subnormal alkaline phosphatase levels may indicate the presence of hypophosphatasia, Wilson's disease, deficiencies of divalent ions, or malnutrition. Subnormal levels of gamma glutamyl transferase may be seen in cases of acute intrahepatic cholestasis, the use of certain medications, and in bone disease. Finally, subnormal levels of 5'-nucleotidase have been reported in lead poisoning and nonspherocytic hemolytic anemia. The aim of this review is to bring attention to the fact that subnormal levels of these enzymes should not be ignored as they may indicate pathological conditions and provide a means of early diagnosis.

Effects of silymarin supplementation on liver and kidney functions: A systematic review and dose-response meta-analysis.

It is suggested that supplementation with silymarin (SIL) has beneficial impacts on kidney and liver functions. This systematic review and dose-response meta-analysis assessed the impact of SIL administration on certain hepatic, renal, and oxidative stress markers. A systematic search was conducted in various databases to identify relevant trials published until January 2023. Randomized controlled trials (RCTs) that evaluated the effects of SIL on kidney and liver markers were included. A random-effects model was used for the analysis and 41 RCTs were included. The pooled results indicated that SIL supplementation led to a significant reduction in serum levels of alkaline phosphatase, alanine transaminase, creatinine, and aspartate aminotransferase, along with a substantial elevation in serum glutathione in the SIL-treated group compared to their untreated counterparts. In addition, there was a nonsignificant decrease in serum levels of gamma-glutamyl transferase, malondialdehyde (MDA), total bilirubin, albumin (Alb), total antioxidant capacity, and blood urea nitrogen. Sub-group analyses revealed a considerable decline in MDA and Alb serum values among SIL-treated participants with liver disease in trials with a longer duration (≥12 weeks). These findings suggest that SIL may ameliorate certain liver markers with potential hepatoprotective effects, specifically with long-term and high-dose supplementation. However, its nephroprotective effects and impact on oxidative stress markers were not observed. Additional high-quality RCTs with longer durations are required to determine the clinical efficacy of SIL supplementation on renal and oxidative stress markers.