Liver Enzymes Research Articles

Lactate dehydrogenase as a biochemical marker for prediction of maternal and perinatal outcomes in hypertensive disorders in pregnancy

Hypertensive disorder of pregnancy includes new onset hypertension in pregnancy that is gestational hypertension and already existing hypertension that is chronic hypertension and gestational hypertension sometimes worsened by preeclampsia. Preeclampsia can cause complications such as eclampsia, HELLP syndrome, renal failure, pulmonary edema, stroke, and left ventricular failure. We aim to assessthe predictive role ofLactate Dehydrogenase value in Hypertensive disorders in pregnancy.After obtaining the informed consent, pregnant patients who were visiting Tertiary care centre and who were more than 28 weeks period of gestation were enrolled. Patients from both antenatal OPD clinics and from those who were presenting in emergency were included in this study. Serum levels of LDH were tested. Patients were monitored till delivery and 6 weeks following childbirth.The Mean serum levels of lactate dehydrogenase (LDH) in eclamptic group was 1495.000±859.1230, 804.569±224.5519 in severely preeclamptic group and in mild preeclamptic group ,mean LDH levels were 520.062±110.3944. The difference between both the groups was statistically significant (p < 0.001).Women with serum LDH levels > 800 IU/L and LDH levels between 601-800 IU/L, experienced considerably greater complications in preeclamptic-eclamptic group as compared to those with serum LDH levels < 600 IU/L.Thepreeclamptic-eclamptic group of women had increased serum LDH levels. Greater LDH levels were linked to worse outcomes for mothers including placental abruption, hemolysis elevated liver enzymes low platelet count (HELLP syndrome), pulmonary edema and maternal death and they were also linked to fetal complications including intrauterine fetal death (IUFD), intrauterine growth restriction and neonatal intensive care unit (NICU) admission.

Influence of pharmacotherapy on function of biotransformation of xenobiotics liver in patients with neuropsychiatric disorders

BACKGROUND: The mechanisms of drug interactions of psychotropic drugs are associated with the processes of drug biotransformation by enzymes of microsomal oxidation of cytochrome P-450 in the liver. Various drugs can increase or decrease the activity of enzymes of the cytochrome P450-dependent system. AIM: To evaluate the effect of pharmacotherapy with psychotropic drugs: alprazolam, bromazepam, lithium carbonate on the metabolic rate of the model substrate antipyrine in saliva in patients with neuropsychiatric disorders; the effect of the enzyme-inducing activity of the original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in healthy volunteers. MATERIALS AND METHODS: 34 male patients were divided into three groups according to the nosological forms of diseases according to ICD-10: Group 1 — heading F43.23 and F43.25; 2 — F06.61; 3 — F41.2. Patients in the group 1 were prescribed alprazolam, in the 2 — bromazepam, in the 3 — lithium carbonate, for a course of 21 days. The comparison group consisted of 10 healthy volunteers. The original anticonvulsant was prescribed to the volunteers. Determination of the pharmacokinetics of antipyrine parameters as a test witness of the processes of elimination from the body was carried out in saliva before and after the end of therapy at a dose of 10 mg/kg once. RESULTS: Alprazolam administration by patients of group 1 at a dose of 0.5–1.5 mg/day for 21 days did not significantly affect the pharmacokinetic parameters of antipyrine: T1/2, Clt, AUC. Alprazolam did not change the elimination of antipyrine from the saliva of patients. In patients of the group2, who received bromazepam at a dose of 6–12 mg / day,a background decrease in T1/2, an increase in Clt, a decrease in AUC due to concomitant therapy were noted. Comparison of the pharmacokinetic parameters of antipyrine under the influence of bromazepam with background values not reveal significant differences. Therapy with lithium carbonate at a dose of 500–1000 mg/day in patients of the group 3 did not change the parameters of antipyrine elimination. The obtained data indicate that the drugs do not affect the activity of liver microsomal oxidation in patients. The study of the effect of 1-[(3-chlorophenyl)(phenyl)methyl]urea on the pharmacokinetic parameters of antipyrine in volunteers revealed a diametrically opposite result: a significant decrease in T1/2 by 2 times, an increase in Clt and a decrease in AUC, which indicates accelerated elimination of antipyrine from the saliva of the subjects and indicates the induction of liver microsomal oxidation. CONCLUSIONS: Pharmacotherapy using the studied psychotropic drugs in patients is not associated with the induction or inhibition of liver enzymes, which indicates the absence of drug pharmacokinetic interference. The original anticonvulsant 1-[(3-chlorophenyl)(phenyl)methyl]urea stimulated the induction of liver microsomal oxidation in volunteers.

HPB SO17 - A rare case of Goblet cell adenocarcinoma of appendix presenting as primary ampullary tumour

Abstract Background Goblet cell adenocarcinoma (GCA), formerly known as goblet cell carcinoid,is a rare appendiceal tumour with amphicrine differentiation that has distinct morphologic and clinical features compared to carcinomas seen elsewhere in the gastrointestinal tract. The tumour histologically resembles both carcinoids and adenocarcinomas. It is found in 0.3–0.9 % of appendectomy specimens; hence, ampullary GCAs are exceptionally uncommon. Method A 57-year-old Caucasian male presented with a two-month history of weight loss, pruritus, and dark urine. His blood tests revealed deranged liver enzymes. His past medical history was unremarkable. Abdominal CT identified a double duct sign, no detectable mass. Endoscopic ultrasound (EUS) revealed a dilated biliary system terminating in a slightly enlarged ampulla (15mm) without any obvious mass lesions. Endoscopic retrograde cholangiopancreatography (ERCP) was performed showing a distal common bile duct (CBD) stricture. Cytology samples were negative for malignancy, and stents were placed in the CBD and pancreatic duct (PD). Pancreaticoduodenectomy was advised given the high risk of malignancy. Results Histopathology report showed clusters of goblet-like mucinous cells in an infiltrative pattern, in addition to classic neuroendocrine tumor morphology, reminiscent of goblet cell adenocarcinoma of the appendix, staged as pT3pN1M0. This is consistent with primary ampullary GCA given the normal appendix on preoprative CT imaging. Conclusion To our knowledge, this is the fourth case of ampullary GCA report in medical literature. There is no consensus on adjunct chemotherapy regimen for systemic treatment. Chicago consensus group (2018) recommends following the colorectal cancer pathway for goblet cell adenocarcinoma. In our experience, given the anatomical location of the tumour and the normal appendix, FOLFIRINOX was offered in line with ampullary adenocarcinoma cancer pathway.

Ultrasound evaluation of kidney and liver involvement in Bardet–Biedl syndrome

Abstract Background Bardet–Biedl syndrome (BBS) is a rare autosomal-recessive ciliopathy with pathogenic variants in 26 BBS genes. It affects multiple organs, including the kidney and liver, with varying degrees regarding extent and time of first manifestation. Structural renal anomalies are an early feature and end-stage kidney disease (ESKD) cumulates to 25% in adulthood. Early-onset hyperphagia-associated obesity is another major symptom and contributes to liver pathology, presenting as steatosis/fibrosis. Aim of this study is the evaluation of high-end ultrasound (US) technologies in BBS patients regarding their potential to discriminate liver and kidney tissue pathology at an early stage. Materials and methods Patients with genetically proven BBS were recruited from the University Children’s Hospital of Essen and from BBS patient days hosted in Germany. Acute illness was an exclusion criterion. Clinical and laboratory data were extracted from patients’ digital records or medical letters. High-resolution ultrasound (US) imaging was utilized, including attenuation imaging (ATI), shear wave elastography (SWE) and dispersion (SWD) of liver tissue. Results 49 BBS patients (24/49 male; 1.1–51.0 years, mean 17.8 years) were included in the study. Mean body weight (SDS 2.13 ± 1.33) and BMI (SDS 2.64 ± 1.18) were increased. Structural kidney abnormalities (dysplasia, cysts) were present in 75% (36/48), and persistent fetal lobulation in 44% (21/48). Renal function was impaired in 27% (13/49) of whom 3 had ESKD (kidney transplantation (n = 2), hemodialysis (n = 1)). Elevation of liver enzymes was detected in 38% (16/42). In 51% (25/49) ATI of liver tissue was increased, indicating hepatic steatosis, and correlated with BMI SDS, liver size, and enzymes. SWE was elevated in 61% (30/49), suggesting hepatic fibrosis, and it correlated with BMI and GGT. Patients with pathogenic variants in BBS10 showed a tendency towards higher ATI, reduced GFR, and higher BMI SDS. Conclusions We detected kidney and liver abnormalities in a higher percentage of BBS patients than previously reported, indicating a high sensitivity and diagnostic yield of the evaluated high-end US applications. ATI detected liver pathology early (partially prior to liver enzymes) and revealed differences related to the affected genes. Evidence of tissue pathology at an early stage may improve diagnostics and the evaluation of therapeutic approaches.

Primary Biliary Cholangitis: Personalizing Second-Line Therapies-R1

Primary biliary cholangitis (PBC) is an enigmatic, autoimmune disease targeting the small intralobular bile ducts resulting in cholestasis and potentially progression to biliary cirrhosis. Primarily affecting middle-aged women, the diagnosis of PBC is typically straightforward with most patients presenting with cholestatic liver tests and the highly specific anti-mitochondrial antibody. For decades, the foundational treatment of PBC has been ursodeoxycholic acid (UDCA) which delays disease progression in most patients but has no impact on PBC symptoms. Large cohort studies of patients with PBC have established the benefit of maximizing the reduction in serum alkaline phosphatase with UDCA and the need to add second-line agents in patients who do not achieve an adequate response. Advances in the understanding of bile acid physiology have led to the development of new agents that improve cholestasis in patients with PBC and are predicted to reduce the risk of disease progression. Obeticholic acid, the first second-line therapy to be approved for PBC, significantly improves liver biochemistries and has been associated with improved long term clinical outcomes but is limited by its propensity to induce pruritus. Elafibranor and seladelpar are peroxisome proliferator-activated receptor agonists recently approved for use in patient with PBC, whereas bezafibrate and fenofibrate are available as off-label therapies. They also have shown biochemical improvements among patients with an inadequate response to UDCA, but may improve symptoms of pruritus. Herein, we review the patient features to consider when deciding whether a second-line agent is indicated and which agent to consider for a truly personalized approach to PBC patient care.

German Real-World Experience of Patients with Diverse Features of Acute Intermittent Porphyria Treated with Givosiran

Background/Objectives: Acute intermittent porphyria (AIP) is a metabolic disease characterised by neurovisceral crises with episodes of acute abdominal pain alongside life-altering, and often hidden, chronic symptoms. The elimination of precipitating factors, hemin therapy, and pain relief are strategies used to treat porphyria symptoms, but are often reserved for patients suffering recurrent, acute attacks. Givosiran (siRNA) is an emerging AIP therapy capable of silencing delta-aminolevulinic acid synthase-1 (ALAS1) and, in turn, reducing the accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) that precede porphyria symptoms. The aim of this study was to investigate the efficacy and safety of givosiran administration in patients with both acute and chronic AIP burden, who were poorly responsive to current therapies, using a personalised medicine approach. Methods: Real-world data were collected in consecutive patients treated with givosiran at an accredited German Porphyria Clinical Center. Biochemical, clinical, and HR-QoL outcomes were monitored alongside adverse events (AEs). Results: Twenty-eight patients treated between 2018 and 2024 were sub-categorised into groups corresponding to Ipnet terms 13 ‘Sporadic Attacks, 5 ‘Symptomatic High Excretors’, 5 ‘Prophylactic Heme’, and 5 “Recurrent Attacks’. The mean time from diagnosis to treatment was 9.2 years (range in months 1–324), and the mean duration of treatment was 30 months (range 3–68). After 6 months of monthly givosiran injection (2.5 mg/kg), all patients’ ALA levels reached <2ULN, and 60% of patients attained PBG levels < 2ULN (p < 0.001). These biochemical responses were not different between sub-groups (p > 0.05). Clinically, 75% of patients’ chronic and acute porphyria symptoms improved. The total patient populations’ annualised attack ratio (AAR) improved; Historical AAR: 2.9 (0–12.0) vs. Givo AAR: 0.45 (0–3.0) (p < 0.01). During follow-up, nine patients experienced minor breakthrough episodes. Of these, three patients required hemin infusion. An association between clinical success and a shorter interim period between diagnosis and treatment was evident (r = −0.522, p = 0.0061). All patients’ indices of HR-QoL improved under givosiran, including mental health (38%, p < 0.0001) and pain (38%, p < 0.0001). Patient-reported health (givosiran 77.9% vs. baseline 37.1%, p < 0.0001) and clinical outcome scores (86.9%: good–very good) were also positive. Two patients withdrew from treatment <6 months, citing fatigue, which was a common side effect. A mild elevation in liver enzymes (AST and/or ALT < 1.5ULN, 15.4%) and reduced glomerular filtration rates (GFR, 11.5%) were also evident, but no life-threatening adverse events (AEs) were attributed to givosiran treatment. Conclusions: Givosiran is effective in preventing severe acute attacks and reducing the chronic health burden in patients with acute intermittent porphyria. Importantly, HR-QoL improved in patients suffering chronic AIP burden with few incidences of historical attacks. All patients experienced substantially improved mental health, ease of living, and self-perceived health.

Correlation of Liver Fibroscan Results with Liver Elastographyand Liver Enzymes in Patients with Fatty Liver

Background: Accurate diagnosis of fatty liver is crucial for prognosis and treatment planning. Objectives: This study aimed to correlate liver fibroscan results with shear wave elastography and liver enzyme levels in fatty liver patients. Methods: In a cross-sectional study, 80 fatty liver patients from Shahid Motahari Clinic in Shiraz was examined over six months. Diagnoses were made using fibroscan (Echosense 500) and CAP scores, while the Hepatorenal Index was measured with shear wave elastography (Sypersonic, Aixplorer elit). Previous sonography reports were collected for correlation. Results: Patients’ average age was 50.91 years so that 45% were men, and 55% were women. About 78.8% diagnosed with fatty liver by ultrasound were also diagnosed by elastography (true positive). A weak, non-significant positive correlation was observed between the Ratio and CAP score (r = 0.18, P = 0.87). ALT predicted fatty liver by elastography with 83.6% sensitivity and 64.7% specificity. Few studies in Iran have explored elastography and fibroscan correlation in fatty liver. Conclusions: Shear wave elastography is a valuable non-invasive technique for predicting fatty liver.

Can We Better Understand, Diagnose, and Treat Ketamine‐Induced Uropathy, and Can It Be Reversed? ICI‐RS 2024

ABSTRACTIntroductionKetamine, a versatile anesthetic, has seen increased recreational use, leading to significant health issues, including ketamine‐induced uropathy (KIU). KIU manifests with lower urinary tract symptoms (LUTS) and can involve the upper urinary tract. This study aims to provide a comprehensive overview of KIU, addressing its pathophysiology, diagnostic strategies, and treatment options; and to define/identify future research priorities.MethodsDuring the 2024 meeting of the International Consultation on Incontinence Research Society (ICI‐RS) in Bristol, a dedicated Proposal (P) convened to explore KIU. This initiative involved a thorough review of existing literature, expert presentations, and consensus‐driven discussions. The methodology ensured a comprehensive exploration of KIU from both clinical and pre‐clinical perspectives, leading to actionable research recommendations.ResultsUnderstanding the mechanisms of KIU is crucial for developing effective treatment options targeting specific pathophysiological pathways. Key findings include bladder fibrosis driven by transforming growth factor‐β1 (TGF‐β1), elevated purinergic responses and upregulated P2X1 purinoceptor expression, decreased barrier function due to increased expression of antiproliferative factor (APF), and functional loss of the bladder through Cav1.2 channel blockade. Research indicates that fibrosis, typically considered irreversible, may be mitigated. However, the exact timing and extent of fibrosis initiation and its impact on long‐term outcomes require further research. LUTS typically improve after ketamine cessation but relapse upon resumption, indicating a hypersensitivity mechanism involving elevated serum IgE levels. Advanced stages of KIU do not always correlate with LUTS severity, shedding light on potential systemic effects and the need for evaluating liver enzymes. Furthermore, psychological dependency on ketamine, due to its positive perceptive and mood‐altering effects, complicates cessation efforts. Long‐term management requires a holistic approach, integrating medical treatments and supportive measures to help patients navigate life with potentially irreversible complications.ConclusionThis comprehensive review spans from fundamental pathology to practical clinical management, addressing both urological and systemic complications, and bridging insights from animal models to human applications. Developing effective treatment strategies necessitates addressing both the physical and psychological aspects of ketamine dependency.

Pharmacological management of pediatric metabolic dysfunction‐associated steatotic liver disease

AbstractPediatric obesity, characterized by a body mass index (BMI) at or above the 95th percentile for age, affects a substantial number of children and adolescents worldwide. Metabolic dysfunction‐associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, represents a prominent hepatic manifestation of obesity and metabolic syndrome, emerging as the most prevalent hepatic disorder among pediatric patients and a significant contributor to liver transplantation in adults. The escalating prevalence of pediatric MASLD mirrors the alarming rise in childhood obesity rates over recent decades. While lifestyle modifications focusing on dietary changes and increased physical activity constitute the cornerstone of MASLD management, achieving and maintaining significant weight reduction remains challenging. Moreover, disease progression often persists despite standard‐of‐care interventions, warranting exploration into alternative therapeutic strategies. Pharmacological interventions, particularly, glucagon‐like peptide‐1 receptor agonists (GLP‐1RA), have shown promise in addressing pediatric obesity and its associated comorbidities, including MASLD. Recent studies have demonstrated the efficacy of GLP‐1RA in inducing weight loss and improving liver enzyme levels, suggesting a potential role in halting disease progression, and reducing the risk of major adverse liver outcomes. This review provides a comprehensive overview of the current pharmacotherapy landscape for pediatric MASLD, with a focus on novel agents such as GLP‐1RA. Furthermore, the manuscript proposes a practical algorithm to assist in integrating GLP‐1RA into the clinical management of pediatric patients with obesity and MASLD. Despite promising results, further research is warranted to elucidate the long‐term efficacy and safety of GLP‐1RA in pediatric populations.

Pre‐ADMET studies of 5‐(3′,4′‐dihydroxyphenyl)‐γ‐valerolactone, the bioactive intestinal metabolite of proanthocyanidins

Abstract5‐(3′,4′‐Dihydroxyphenyl)‐γ‐valerolactone (VL) is a bioactive metabolite resulting from the gut microbial metabolism of proanthocyanidins and flavonoids, known for its health‐promoting effects, including antidiabetic and anti‐inflammatory activities. Although VL has been observed in different in vivo studies, its pre‐absorption, distribution, metabolism, excretion, toxicity (ADMET) properties have rarely been investigated. This study aims to address this gap by evaluating the pre‐ADMET properties of VL for the first time. Also, the understanding of these properties is significant for correlating the encountered activities to this metabolite. In vitro absorption studies revealed that VL is rapidly metabolized and absorbed as its sulfate phase II conjugate (valerolactone sulfate), which enters systemic circulation and mildly activates the Breast Cancer Resistance Protein efflux transporter. In human S9 liver fraction, a mixture of liver enzymes used to simulate in vivo liver metabolism, VL is metabolized into glucuronic phase II conjugates (valerolactone glucuronide 1 [VLG1] and 2 [VLG2]) with a half‐life of 8.72 min and an 80% conversion rate. In human liver microsomes, VL is metabolized at a slower rate (half‐life of 23.08 min), suggesting that oxidative metabolism is secondary. Additionally, VL did not activate the pregnane X receptor or inhibit Cytochrome P3A4 (CYP3A4) and Cytochrome P1A2 (CYP1A2) enzymes, indicating no risk of herb–drug interactions with coadministered prescription drugs.

Feeding chicory silage, but not Se-yeast or a single injection of inorganic Se, affects metabolism, fat in milk, and type I immunity in transition ewes

In the study, we assessed the effect on performance and health of a single injection of inorganic Se prepartum or feeding chicory silage and organic Se supplementation during the peripartum in ewes. Approximately one month before lambing, 45 pregnant Polypay ewes were moved into single pens and randomly assigned to 5 groups to be fed either grass or chicory silage and supplemented or not with 3.6 mg Se/day as selenium yeast or given a single prepartum injection of Na-selenite. Daily dry matter intake (DMI), water intake, milk production and components, blood metabolic, immune and inflammatory parameters, and blood micromineral levels were measured. DMI was lower in ewes fed chicory silage, although no statistical differences in milk yield were observed. Very few differences were observed in milk components, except fat %, which was higher among ewes fed chicory silage. The type of silage had a significant effect on the fatty acid profile of the milk, with the milk from ewes fed chicory having a higher proportion of unsaturated fatty acids and overall improved health indices compared to the milk from ewes fed grass silage. Blood NEFA and BHBA were higher in ewes fed chicory vs. grass silage. Neither silage type nor Se supplementation had a strong effect on most of the parameters associated with immune or inflammatory function, except for the liver enzymes GGT and GOT, which were lower, and a larger type I/type II ratio immune response measured by the DxD2 assay among ewes fed chicory vs. grass silage. No effects on parasite fecal egg counts were observed. Supplementation of ewes with Se-yeast resulted in higher blood levels of Se, whereas the one-time prepartum injection had no significant effect on whole blood Se levels. Feeding chicory silage and supplementing Se during the transition period had a minimal impact on ewe performance and health.

Oral administration of tannic acid attenuates dyslipidemia, hyperglycemia, and oxidative stress in high‐fat and fructose diet‐induced obesity in rats

AbstractObesity and diabetes are considered life‐threatening conditions, characterized by increased oxidative stress, insulin resistance, hepatotoxicity, hyperglycemia, and hypercholesterolemia. Therefore, we studied the effects of tannic acid in a high‐fat and fructose‐diet‐induced rat model of obesity. Administration of tannic acid at doses of 200 and 400 mg/kg significantly reduced fasting blood glucose concentration, reversed disoriented lipid profile, decreased liver enzyme activities, and inhibited oxidative stress compared to the high‐fat, high‐sugar group. Histopathological examination showed preserved pancreas and liver architecture in the tannic acid‐administered groups. The in vitro inhibitory activity of tannic acid against alpha‐amylase, alpha‐glucosidase, and pancreatic lipase showed good inhibitory potential. Molecular docking studies showed high binding affinity and more hydrogen bond interactions between tannic acid and receptor proteins (alpha‐amylase, alpha‐glucosidase, and pancreatic lipase) implicated in obesity and diabetes. In conclusion, tannic acid prevented the onset of oxidative stress, preserved the liver, and restored the disoriented lipid profile in high‐fat and fructose diet‐induced obesity in rats.

QOL-29. PREVALENCE, MANAGEMENT, AND OUTCOMES OF PROCARBAZINE-ASSOCIATED HYPERSENSITIVITY REACTIONS IN PATIENTS RECEIVING PCV FOR LOW-GRADE GLIOMA

Abstract Procarbazine is an alkylating agent commonly used to treat low-grade gliomas as part of the PCV regimen. The use of procarbazine is frequently limited by the development of hypersensitivity reactions (HSRs), which often require dose reduction or cessation of procarbazine therapy prior to the completion of a planned treatment course. The prevalence, clinical characteristics, and potential predictors of these reactions are not well defined. We conducted a retrospective cohort study of patients with low-grade glioma who received PCV between January 2016 and January 2024 at a tertiary academic hospital. Data on patient demographics, tumor type, clinical characteristics, treatment course, and hypersensitivity reactions were collected and analyzed. 61 total patients were included. The overall prevalence of HSRs was 60.7% (95% CI: 48.4% - 72.9%). The median cycle during which HSRs occurred was cycle 3 (IQR: 2-4, Range: 1-5). All HSRs involved the development of rash, with 86.5% being pruritic and 21.6% involving the face. Treatments for HSRs included antihistamines (62.2%), topical corticosteroids (35.1%), and systemic corticosteroids (27.0%). Three patients with HSRs presented to the emergency department with concern for anaphylaxis, and one required treatment with epinephrine. Out of six patients rechallenged with procarbazine after experiencing HSRs, one patient redeveloped a diffuse, pruritic rash that resolved with systemic corticosteroids. A multiple logistic regression analysis was performed to assess the association between HSRs and gender, age at PCV C1D1, elevated liver enzymes, and concomitant anticonvulsant use, but no significant correlation was observed. In summary, our study provides a contemporary and comprehensive analysis of the prevalence and severity of HSRs to procarbazine in patients with low-grade glioma. The high rate of HSRs in this population, including a relatively high rate of suspected anaphylaxis, should be considered carefully by clinicians in choosing chemotherapy for low-grade glioma and warrants routine counseling and close monitoring.

CYP3A4*1B and CYP3A5*3 SNPs significantly impact the response of Egyptian candidates to high-intensity statin therapy to atorvastatin

BackgroundA single nucleotide polymorphism (SNP) is a variation in the DNA sequence that results from the alteration of a single nucleotide in the genome. Atorvastatin is used to treat hypercholesterolemia. It belongs to a class of drugs called statins, which lower elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Research findings on the associations between the response to atorvastatin and genetic polymorphisms in CYP3A4 and CYP3A5 are inconclusive. The effects of CYP3A4*1B (rs2740574 C/T) and CYP3A5*3 (rs776746 T/C) on atorvastatin therapy have not been previously studied among Egyptians.ObjectiveThis research aimed to investigate the effects of the genetic polymorphisms CYP3A4*1B and CYP3A5*3 on atorvastatin treatment in Egyptians.MethodsIn this prospective cohort study, 100 subjects were genotyped for these SNPs. All participants were screened for serum lipid profiles, liver enzymes, total bilirubin (TB), and creatine kinase (CK) before and after 40 mg postatorvastatin therapy. Atorvastatin plasma levels were assessed posttreatment; atorvastatin pharmacokinetics were evaluated in five carriers of the CYP3A4*1B (T/T) and CYP3A5*3 (C/C) genotypes.ResultsThe allele frequencies of the CYP3A4*1B and CYP3A5*3 SNPs were 86% and 83%, respectively. The CYP3A4*1B (T/T) and CYP3A5*3 (C/C) genotypes significantly improved the serum triglyceride (TG) level (P < 0.05) and elevated the TB level (P < 0.001). Atorvastatin plasma levels were greater in CYP3A4*1B (T/T) (P < 0.05) and CYP3A5*3 (C/C) (P < 0.001) genotype carriers. Both SNPs significantly affected the pharmacokinetics of atorvastatin compared with those of Egyptian volunteers and various ethnic populations.ConclusionsThe CYP3A4*1B and CYP3A5*3 variants were prevalent in the study participants and could impact the effectiveness and safety of atorvastatin therapy. The mutant genotype of the CYP3A4*1B SNP and the CYP3A5*3 SNP led to high atorvastatin levels. Both variants had a notable effect on the pharmacokinetics of atorvastatin among Egyptians compared with healthy Egyptians and volunteers from other ethnic populations. Overall, clinicians can learn more about the impact of both variants in response to atorvastatin.Graphical

DETECTION OF CLINICAL BIOMARKERS ASSOCIATED WITH HEPATO AND RENAL MANIFESTATIONS IN COVID-19 PATIENTS

The COVID-19 pandemic has spread in many countries worldwide, surpassing one million confirmed cases and resulting in deaths globally. Developing nations such as Pakistan face heightened vulnerability to such outbreaks due to limited healthcare infrastructure and resources. This study examines clinical biomarkers linked to hepatic and renal manifestations in COVID-19 patients in North Waziristan, recognizing the vulnerability of developing countries like Pakistan to such pandemics due to limited healthcare resources. Nasopharyngeal swabs were collected from 110 suspected COVID-19 patients visiting Dr. Azim Ullah clinic and DHQ Hospital North Waziristan, Miran Shah. Hematological, hepatic, renal, C-reactive protein (CRP), and ferritin markers were assessed. Most patients were male (75%), with varying age distributions. Abnormalities were observed in hematological parameters, liver enzymes, renal function markers, CRP, and ferritin levels. Significant correlations (p&lt;0.001) were found among these markers. The study concludes that inflammatory, hematological, renal, and liver markers are associated with COVID-19 infection, with higher levels indicating severe disease. Continuous monitoring of these biomarkers may enhance patient outcomes and aid in predicting disease progression

Sodium-Glucose Cotransporter 2 Inhibitors Improve Body Composition by Increasing the Skeletal Muscle Mass/Fat Mass Ratio in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) induce body weight loss, but their effect on skeletal muscle mass (SMM) and strength needs to be better elucidated. Objectives: This study aimed to evaluate the effects of SGLT2i on SMM in a real-life population setting of patients with type 2 diabetes (T2D). Secondary outcomes included changes in liver steatosis and in anthropometric and glucometabolic parameters. Methods: Seventy-one patients were treated with SGLT2is as an add-on to metformin for 52 consecutive weeks. Visits were scheduled at baseline (T0) and after 6 (T6) and 12 months of therapy (T12) and included the checking of laboratory tests, measurement of anthropometric parameters, bioimpedance analysis of body composition, and abdominal ultrasound (US). Results: Fat mass (FM) and visceral adipose tissue (VAT) progressively decreased compared to the baseline (FM: −2.9 ± 0.6 kg at T6; −2.8 ± 0.6 kg at T12; VAT: −0.3 ± 0.1 L at T6; −0.4 ± 0.1 L at T12; all p &lt; 0.01). Changes in SMM were less pronounced (−0.4 ± 0.3 kg at T6, ns; −0.7 ± 0.4 kg at T12, p &lt; 0.05), yielding a beneficial increase in the SMM/FM ratio (+0.3 ± 0.05 at T6 and +0.2 ± 0.05 at T12, all p &lt; 0.01). No significant changes in sarcopenia, sarcopenic obesity, fat-free mass, muscle strength, and water compartments were observed at the end of the follow-up period. Anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and biometric indices and US grading of hepatic steatosis improved throughout this study. Conclusions: In a real-life setting, SGLT2i therapy is associated with weight loss attributable to FM rather than SMM loss without any relevant deterioration in muscle strength. In addition, SGLT2is proved to have beneficial effects on steatotic liver disease.

Biochemical Studies of Averrhoa carambola Ethanol Leaf and Fruit Extracts on Alloxan-induced Diabetic Rats

The use of herbal medicines has always been an option to treat diseases such as diabetes cancer and other ailments. This study aimed to evaluate the effect of Averrhoa carambola leaf and its fruit ethanol extracts on biochemical parameters and histopathology features. Forty five albino rats were assigned into 9 groups of 5 rats each. Except for the normal control group, others were induced to be diabetic by a single intraperitoneal injection of alloxan. Group 1 (normal control) and Group 2 (diabetic untreated) received water. Group 3 received 2.5mg/kg glibenclamide, Groups 4-9 received graded doses (250mg/kg, 500mg/kg and 750mg/kg) of leaf and fruit extracts of Averrhoa carambola. Treatment lasted 14days. At the end of the treatment, blood samples and organ (pancreas) were collected from the animals for biochemical and histopathological evaluation. Treatment of alloxan-induced diabetic rats significantly (p&lt;0.05) reduced the glucose concentration across all treated groups. Following induction of diabetic mellitus, the serum activities of liver enzymes (Alanine amino transferase, Aspartate aminotransferase and Alkaline phosphatase), low-density lipoprotein cholesterol (LDL-C) and triglyceride were significantly (p&lt;0.05) elevated in diabetic untreated group with corresponding reduction in serum protein, albumin and high-density lipoprotein cholesterol (HDL-C) compared to the normal control and treated groups. However, the fruit extracts exhibited a high increase in urea and creatinine levels especially at dose of 750mg/kg body weight when compared with the leaf though not significantly higher than the diabetic untreated group. From histopathology studies, the groups treated with the leaf extract of Averrhoa carambola showed greater structural improvement and an increase in pancreatic islet cells. Therefore this study showed that although ethanol extracts of Averrhoa carambola leaf and fruit have antidiabetic properties, the leaf extract possesses more antidiabetic effect.

The effect of ertugliflozin in patients with nonalcoholic fatty liver disease associated with type 2 diabetes mellitus: A randomized controlled trial

Background: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with liver inflammation, fibrosis, and cirrhosis and is associated with a greater risk of hepatocarcinoma. Nonalcoholic steatohepatitis (NASH) is a persistent and progressive form of NAFLD. Recent evidence suggested that ertugliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2), suppresses NAFLD development in patients with type 2 diabetes mellitus (T2DM). The objective of this study was to determine the impact of ertugliflozin on improving NAFLD in patients with T2DM and the function of liver enzymes. Methods: This prospective, randomized, double-blind, placebo-controlled, interventional study aimed to determine the effectiveness of 15 mg of ertugliflozin versus 30 mg of the standard therapy pioglitazone versus placebo in NAFLD patients with T2DM. The study was established based on patient randomization in three groups: ertugliflozin, pioglitazone, and a placebo. This study was registered under the Australian New Zealand Clinical Trial Registry (Trial ID: ACTRN12624000032550). Results: The impact of therapy was determined in the treatment groups by utilizing liver ultrasonography and biochemical parameters. After 24 weeks of clinical study, the results revealed significant improvement in the grades of fatty liver, especially in the ertugliflozin group. The number of patients with hepatic steatosis significantly decreased among the respective groups classified according to fatty liver grade. Among patients in the ertugliflozin and pioglitazone groups, 45% to 23.4% and 41.7% to 26.6%, respectively, decreased in the Grade 2 group. The aspartate aminotransferase and alanine aminotransferase levels were significantly lower in all the study groups, especially in the ertugliflozin group (P ≤ .001). Conclusion: The present study revealed that the concomitant use of ertugliflozin has favorable effects on liver enzymes, as it decreases liver fat intake and reduces complications in patients with NAFLD-associated T2DM. However, more in-depth studies will be required to observe every aspect of ertugliflozin.

Fatty acid composition evaluation of abdominal adipose tissue using chemical shiftencoded MRI: Association with diabetes.

This study investigated the association between the fatty acid composition of abdominal adipose tissue in NAFLD patients using chemical shift-encoded MRI and the development of insulin resistance and T2DM. We enrolled 231 subjects with NAFLD who underwent both abdominal magnetic resonance spectroscopy and chemical shift-encoded MRI: comprising of 49 T2DM patients and 182 subjects without. MRI- and MRS-based liver fat fraction was measured from a circular region of interest on the right lobe of the liver. The abdominal fatty acid compositions were measured at the umbilical level with chemical shift-encoded MRI. Bland-Altman analysis, Student's t test, Mann-Whitney U test, and Spearman correlation analysis were performed. The logistic regression was applied to identify the independent factors for T2DM. Then, the predictive performance was assessed by Receiver operating characteristic curve analyses. An excellent agreement was found between liver fat fraction measured by MRS and MRI. (slope = 0.8; bias =-0.92%). In, patients with T2DM revealed lower fractions of mono-unsaturated fatty acid (Fmufa) (33.68 ± 10.62 vs 38.62 ± 12.21, P =.0089) and higher fractions of saturated fatty acid (Fsfa) (34.11 ± 9.746 vs 31.25 ± 8.66, P =.0351) of visceral fat tissue compared with patients without. BMI, HDL-c, Fmufa and Fsfa of visceral fat were independent factors for T2DM. Furthermore, Fsfa-S% was positively correlated with liver enzyme levels (P =.003 and 0.04). However, Fmufa-V% was negatively correlated with fasting blood glucose, HbA1c and HOMA-IR (P =.004, P =.001 and P =.03 respectively). Hence, the evaluation of fatty acid compositions of abdominal fat tissue using chemical shift-encoded MRI may have a predictive value for T2DM in patients with NAFLD.

MRNA therapy effective treatment of rare hereditary diseases

mRNA therapy, or mRNA-based drugs that have emerged thanks to vaccines against SARS-CoV-2, have successfully passed preclinical tests and are currently at various stages of clinical trials in the treatment of many diseases, including rare metabolic disorders. In the case of rare genetic metabolic diseases, the concept of mRNA therapy can be considered as an alternative to protein replacement therapy, where exogenous mRNA leads to the production of a fully active protein instead of a non-functional one, and also delivers it to the desired cellular compartment, such as mitochondria or the cell membrane. Preclinical studies on animal models of some rare genetic diseases have fully confrmed the validity of this concept. In this mini-review, we examine and discuss the mentioned preclinical studies on efficacy and safety in several animal models. For all the diseases considered, mRNA therapy restored functional protein to therapeutically significant levels in target organs, led to stable and reproducible results after each dose of mRNA, and was well tolerated, as confirmed by functional liver tests evaluated in animal models, including non-human primates. These data convincingly confirm the potential of clinical development of mRNA therapy for the treatment of various rare metabolic disorders.