Elevated Gamma-glutamyl Transferase Research Articles

The role of impaired glucose and lipid metabolism and liver enzyme abnormalities in the formation of multiple acrochordons: a case-control study

Background Acrochordons, one of skin tumors, are protrusions of the loose fibrous tissue. In various studies, they have found to be associated with abnormal lipid profile, diabetes, cardiovascular disease, obesity, abnormal liver enzymes and genetic factors. In our case-control study, we aimed to determine possible associations of multiple acrochordons with obesity, impaired glucose and lipid metabolism, thyroid disorders, anemia and liver enzymes abnormalities.Methods Sixty-five patients (32 male, 33 female) with at least 8 skin tags and age- and gender-matched 60 controls without skin tags (30 male, 30 female) were enrolled to the study. We noted patients’ and controls’ age, height, weight, body mass index (BMI) and detailed medical history. Locations of acrochordons were recorded for the patient group. We recorded values of fasting plasma glucose, insulin, homeostatic model assessment insulin resistance (HOMA-IR), total cholesterol, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL), free T3 (fT3), free T4 (fT4), thyroid-stimulating hormone (TSH), hemoglobin, ferritin, vitamin B12, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP).Results Our study has shown a genetic predisposition to the development of multiple skin tags (P=0.0001). The mean BMI was statistically significant between the patients and controls (P<0.0001). In addition, we have found that when fasting plasma glucose, AST and GGT levels increase, the possibility of the forming of multiple acrochordons also increases (P=0.048, P=0.003, P=0.013). We determined that increasing of BMI is a risk factor for both genders (P=0.003, P<0.0001, respectively). We found that elevated fasting plasma glucose, insulin, HOMA-IR, total cholesterol, triglyceride, AST, ALT and GGT levels increase possibility of the forming of multiple acrochordons in females (P=0.037, P=0.022, P=0.013, P=0.03, P=0.007, P<0.0001, P=0.015, P=0.005, respectively).Conclusion Our results show that multiple acrochordons may be the cutaneous signs of abnormal glucose and lipid metabolism and liver enzyme abnormalities. Thus, we suggest that clinicians should see appropriate bloodtests for patients with multiple skin tags and manage them accordingly.

Evaluation of a Novel Missense Mutation in ABCB4 Gene Causing Progressive Familial Intrahepatic Cholestasis Type 3.

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a hepatic disorder occurring predominantly in childhood and is difficult to diagnose. PFIC3, being a rare autosomal recessive disease, is caused by genetic mutations in both alleles of ABCB4, resulting in the disruption of the bile secretory pathway. The identification of pathogenic effects resulting from different mutations in ABCB4 is the key to revealing the internal cause of disease. These mutations cause truncation, instability, misfolding, and impaired trafficking of the MDR3 protein. Here, we reported a girl, with a history of intrahepatic cholestasis and progressive liver cirrhosis, with an elevated gamma-glutamyltransferase level. Genetic screening via whole exome sequencing found a novel homozygous missense mutation ABCB4:c.1195G>C:p.V399L, and the patient was diagnosed with PFIC3. Various computational tools predicted the variant to be deleterious and evolutionary conserved. For functional characterization studies, plasmids, encoding ABCB4 wild-type and selected established mutant constructs, were expressed in human embryonic kidney (HEK-293T) and hepatocellular carcinoma (HepG2) cells. In vitro expression analysis observed a reduced expression of mutant protein compared to wild-type protein. We found that ABCB4 wild type was localized at the apical canalicular membrane, while mutant p.V399L showed intracellular retention. Intracellular mistrafficking proteins usually undergo proteasomal or lysosomal degradation. We found that after treatment with proteasomal inhibitor MG132 and lysosomal inhibitor bafilomycin A1, MDR3 expression of V399L was significantly increased. A decrease in MDR3 expression of mutant V399L protein may be a result of proteasomal or lysosomal degradation. Pharmacological modulator cyclosporin A and intracellular low temperature (30°C) treatment significantly rescued both the folding defect and the active maturation of the mutant protein. Our study identified a novel pathogenic mutation which expanded the mutational spectrum of the ABCB4 gene and may contribute to understanding the molecular basis of PFIC3. Therefore, genetic screening plays a conclusive role in the diagnosis of rare heterogenic disorders like PFIC3.

845-P: Changes in Plasma Levels of Liver Enzymes in Response to Dapagliflozin, Metformin, or Exercise in People with Prediabetes: The PRE-D Trial

Background: Plasma levels of liver enzymes are elevated in prediabetes but may improve in response to weight loss and glucose-lowering interventions. We examined the effects of dapagliflozin, metformin, or exercise on plasma levels of alanine transferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) in people with prediabetes. Methods: 120 adults with prediabetes (30-70 years, BMI≥25 kg/m2, HbA1c 5.7-6.4%) were randomized to 13 weeks of dapagliflozin (10 mg once daily), metformin (850 mg twice daily), exercise (30 min, 5 days/week) or control (habitual living). Fasting plasma levels of ALT, AST, and GGT were measured at baseline and after 6 and 13 weeks of intervention and after 26 weeks of follow-up. Linear mixed-effects models were performed. Results: At baseline, median (Q1;Q3) HbA1c was 5.9% (5.7; 6.1). 17% had elevated ALT levels, 3% elevated AST levels, and 6% elevated GGT levels. ALT and AST levels did not change in response to the interventions (Table 1). Small within-group changes in GGT were observed in the active groups after 6, 13 or 26 weeks, but they did not differ from the control group (P≥0.09 for all comparisons). Conclusions: 13 weeks of treatment with dapagliflozin, metformin or exercise was not associated with changes in liver function markers compared with habitual living in people with prediabetes. Disclosure M.B. Blond: None. K.K. Clemmensen: Research Support; Self; AstraZeneca, Novo Nordisk Foundation. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. H. Amadid: None. L.B. Nielsen: None. M. Ried-Larsen: None. K. Karstoft: Employee; Spouse/Partner; Novo Nordisk A/S. F. Persson: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Research Support; Self; Amgen, AstraZeneca, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Mundipharma International, Novo Nordisk A/S. M.E. Jørgensen: Research Support; Self; Amgen, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Sanofi-Aventis. Stock/Shareholder; Self; Novo Nordisk A/S. K. Faerch: None. Funding Novo Nordisk Foundation; AstraZeneca; University of Copenhagen; Innovation Foundation

Combined alcoholic and non-alcoholic steatohepatitis.

SummaryWhile metabolic syndrome and alcohol consumption are the two main causes of chronic liver disease, one of the two conditions is often predominant, with the other acting as a cofactor of morbimortality. It has been shown that obesity and alcohol act synergistically to increase the risk of fibrosis progression, hepatic carcinogenesis and mortality, while genetic polymorphisms can strongly influence disease progression. Based on common pathogenic pathways, there are several potential targets that could be used to treat both diseases; based on the prevalence and incidence of these diseases, new therapies and clinical trials are needed urgently.

Sex- and age-specific variations, temporal trends and metabolic determinants of serum uric acid concentrations in a large population-based Austrian cohort

Little is known about sex- and age-specific variations and temporal trends in serum uric acid (SUA) concentrations, the prevalence of hyperuricemia and its association with metabolic risk factors in the general population. Between January 1, 1985 and June 30, 2005 146,873 participants (42% women) were recruited. Prevalence of hyperuricemia was estimated applying a common (SUA > 360 µmol/L) and sex-specific cut-off points (women > 340 µmol/L, men > 420 µmol/L). At baseline, mean age was 41.2 years in men and 51.5 years in women, mean SUA concentration was 314.8 µmol/L and 243.6 µmol/L, respectively. Applying a common cut-off point, the prevalence of hyperuricemia was 18.5% in men and 4.4% in women and by sex-specific cut-off points it was 15.1% and 13.8%, respectively. SUA levels increased by 6.7 µmol/L per decade in men, but remained constant in women until the age of 50 years with a sharp increase by approximately 22 µmol/L per decade thereafter. In men and women, hyperuricemia was associated with obesity, hypertriglyceridemia and elevated gamma-glutamyl transferase. With increasing age SUA levels and the prevalence of hyperuricemia rise in a sex-specific manner. Above the age of 65 years, the sex-specific prevalence of hyperuricemia in women outreaches that in men.

Role of Gamma Glutamyltransferase and Alkaline Phosphatase Assay in Enzymatic Panel for Hepatobiliary Function in Patients Attending Kibungo Hospital, Rwanda

Background: Liver complications show specific processes like hepatoxicity associated with drugs, primary neoplasm, or hepatotropic virus infections. Different markers based on laboratory testing help to diagnose and monitor liver related conditions. Mostly used tests are classed in a set known as hepatic panel or liver profile mainly consisting of body enzymes.Objective: The objective of the present study was to ascertain the role of gamma glutamyltransferase (GGT) and alkaline phosphatase (ALP) assay in enzymatic panel for hepatobiliary function assessment among patients attending Kibungo hospital.Methods: Two hundred twenty-five clients were included in the study. Demographic data were collected from December 2016 to March 2017. Blood sera were also collected and tested for serum GGT and ALP levels. Statistical package for social sciences (SPSS) was used in data analysis.Results: Seventy-four point seven per cent of clients had normal GGT whereas 63.1% had normal ALP. The 0.9% of clients comprised low levels of ALP. The means were 53 and 153 U/L for GGT and ALP, respectively. Fifty per cent of alcohol consumers’ population had elevated GGT and ALP. An increase of 69.2 and 61.5% for GGT and ALP, respectively was observed in smokers’ population. The subpopulation of hepatitis C virus (HCV) was the most with elevated GGT and ALP levels. In HIV population, serum GGT and ALP were raised at 31.1 and 37.8%, respectively. In fact, hepatitis B virus (HBV), HCV, and HIV patients are clinically considered as immuno-compromised people. Alcohol consumption and smoking were also found to increase GGT and ALP concentrations. In addition, GGT and ALP levels were simultaneously elevated in 19.6% of the clients, indicating the frequency of cholestatic liver disease.Conclusion: Elevated GGT and ALP revealed the occurrence of cholestasis among study participants due to factors that elevate serum GGT and ALP levels as a result of dysfunctional liver conditions. In hospital laboratories, GGT and ALP should always be included in the panel of tests for screening and bio-monitoring liver related conditions in Rwanda.

Gamma glutamyl transferase - an underestimated marker for cardiovascular disease and the metabolic syndrome.

Gamma glutamyl transferase (GGT) is an enzyme in glutathione and cysteine metabolism. GGT is a standard liver enzyme test reflecting biliary tract involvement. It also has a prooxoidant activity and a modulating influence on endothelia dysfunction. GGT is associated with the metabolic syndrome and is often elevated in patients with NAFLD. There is also a role for GGT activity in several aspects cardiovascular disease. There is an association between elevated GGT and cardiovascular mortality, atrial fibrillation, exacerbation of congestive heart failure . In addition there is an association with obstructive sleep apnea. We review the evidence available and suggest that there is a need for further assessing the use of GGT, together with the presence of the metabolic syndrome as a prognostic marker.

Novel Percutaneous Image-guided Treatment of Choledocholithiasis in a 30-Day-old Infant.

Novel Percutaneous Image-guided Treatment of Choledocholithiasis in a 30-Day-old Infant.

Risk factors and management of different types of biliary injuries in blunt abdominal trauma: Single-center retrospective cohort study.

BackgroundBiliary injuries after blunt abdominal traumas are uncommon and difficult to be predicted for early management. The aim of this study is to analyze the risk factors and management of biliary injuries with blunt abdominal trauma.MethodPatients with blunt liver trauma in the period between 2009 to May 2019 were included in the study. Patients were divided into 2 groups for comparison; a group of liver parenchymal injury and group with traumatic biliary injuries (TBI).ResultsOne hundred and eight patients had blunt liver trauma (46 patients with liver parenchymal injury and 62 patients with TBI). TBI were; 55 patients with bile leak, 3 patients with haemobilia, and 4 patients with late obstructive jaundice. Eight patients with major bile leak and 12 patients with minor bile leak had been resolved with a surgical drain or percutaneous pigtail drainage. Nineteen patients (34.5%) with major and minor bile leak underwent successful endoscopic retrograde cholangiopancreatography (ERCP). Sixteen patients (29.1%) underwent surgical repair for bile leak. In Multivariate analysis, the possible risk factors for prediction of biliary injuries were central liver injuries (P = 0.032), high grades liver trauma (P = 0.046), elevated serum level of bilirubin at time of admission (P = 0.019), and elevated gamma glutamyl transferase (GGT) at time of admission (P = 0.017).ConclusionHigh-grade liver trauma, central parenchymal laceration and elevated serum level of bilirubin and GGT are possible risk factors for the prediction of TBI. Bile leak after blunt trauma can be treated conservatively, while ERCP is indicated after failure of external drainage.

Implications of abnormal liver function in pregnancy and non-alcoholic fatty liver disease.

Elevated liver enzyme levels can sometimes be encountered in asymptomatic pregnant women. Similar to non-pregnant subjects, women with elevated gamma glutamyltransferase or alanine aminotransferase in early pregnancy have increased risk of subsequent complications, especially gestational diabetes mellitus. In non-pregnant subjects, the commonest cause of abnormal liver function currently is non-alcoholic fatty liver disease. Risk factors include obesity, diabetes, and the metabolic syndrome. It can progress to hepatocellular carcinoma through the development of steatohepatitis, and has become the leading cause for liver transplantation in women. Found in as many as 16-18% of pregnant women, it is associated with an increased risk of pregnancy complications and abnormal foetal growth, which predisposes the offspring to the same problem subsequently. This condition probably explains the majority of the cases of "idiopathic" abnormal liver function in pregnancy, and should be looked out for in high-risk women owing to its implications on their long-term health outcome.

Risk factors of silent allograft fibrosis 10 years post-pediatric liver transplantation

This study analyzed factors related to allograft fibrosis in clinically stable pediatric liver transplantation patients. Pediatric patients who underwent liver transplantation from January 1997 to January 2008 and further underwent 10-year protocol biopsies were examined. Grades of inflammation and fibrosis were classified based on Banff criteria and the Liver Allograft Scoring (LAF) system, respectively. Risk factors for fibrosis were analyzed using logistic regression. Sixty-six patients with no clinical signs of chronic liver disease were included. Forty-one patients out of 66 (62.1%) had certain stage of allograft fibrosis. More than five events with aminotransferase >50 U/L was a risk factor for a LAF score 1–2 portal fibrosis (OR = 3.156, CI 1.059–9.410, P = 0.039). More than five events with aminotransferase >100 U/L was a risk factor for LAF score 2 portal fibrosis (OR = 13.978, CI 2.025–97.460, P = 0.007) and LAF score 1–2 sinusoidal fibrosis (OR = 4.897, CI 1.167–20.548, P = 0.030). Positive autoantibody (OR = 3.298, CI 1.039–10.473, P = 0.043) and gamma-glutamyl transferase 60 U/L (OR = 6.201, CI 1.096–35.097, P = 0.039) were related to sinusoidal fibrosis with LAF score of 1–2 and 2, respectively. Experience of post-transplantation lymphoproliferative disease was related to LAF score 1–2 portal fibrosis (OR = 7.371, CI 1.320–41,170, P = 0.023) and LAF score 1–2 centrolobular fibrosis (OR = 8.822, CI = 1.378–56.455, P = 0.022). Our results indicate that liver fibrosis is common in patients with no clinical signs of graft deterioration and repeated elevation of aminotransferases, positive autoantibodies, elevated gamma-glutamyl transferase and experience of post-transplantation lymphoproliferative disease are suspicious signs for fibrosis.

Homozygous NEK8 Mutations in Siblings With Neonatal Cholestasis Progressing to End‐stage Liver, Renal, and Cardiac Disease

Homozygous <i>NEK8</i> Mutations in Siblings With Neonatal Cholestasis Progressing to End‐stage Liver, Renal, and Cardiac Disease

Evaluation of Gamma glutamyl-transferase (GGT) levels in COVID-19: A retrospective analysis in tertiary care centre

Many recent studies have reported that patients infected with novel coronavirus 2019 or SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) might have a liver injury. However, few studies have focussed on the levels of Gamma glutamyl-transferase (GGT) alone and the variations associated with it. We retrospectively analysed the GGT levels of 476 admitted patients with confirmed COVID-19 in a tertiary care centre, PGIMER (Post Graduate Institute of Medical Education and Research), Chandigarh. Out of the total 476 COVID-19 patients studied, 35% had elevated GGT levels. ICU care was required for 51.19% (P <0.0001) of these patients and their hospital stay was of longer duration as compared to the patients with normal GGT levels. The incidence of GGT elevation was found to be more pronounced in males and elderly patients. The male population displayed higher GGT levels with 52% having raised levels compared to females where only 21.6% had elevated GGT levels. Although the number of COVID-19 cases was majorly from young age groups, the elevation in GGT levels has been reported more in elderly patients. GGT levels can therefore serve as a predictor for the extent of liver injury and severity in COVID-19 patients.

Atypical cystic hepatocellular carcinoma in a Himalayan cat

A liver mass was incidentally revealed in a 10-year-old male neutered Himalayan cat on radiographic examination conducted in a local animal hospital. The abdominal distention had worsened over the past five months, along with intermittent vomiting and nausea for two weeks. Serum chemistry was unremarkable, except for elevated alkaline phosphatase and gamma-glutamyl transferase levels. Radiography revealed a round-shaped soft mass in the cranial abdomen. Abdominal ultrasonography showed a well defined, massive, fluid-filled cyst with multiple lobes, and heterogeneous echogenicity in the pancreas. Computed tomography examination revealed hypoplasia of the left lobes of the liver, but the vascular changes and enhancement of the mass were not observed on contrast computed tomography images. The herniation of the abdominal fat through the diaphragm was incidentally observed on sonography and computed tomography scan. The patient was tentatively diagnosed with pancreatic cyst. The laparotomy revealed that the origin was not related to the pancreas, but was suspended from the liver. The mass was multilobular and filled with approximately 120 ml of fluid containing a few white blood cells. The patient recovered from anesthesia, but showed postoperative respiratory depression and died of cardiac arrest 15 hours later. Histopathologically, the mass was definitively diagnosed to be hepatic cellular carcinoma.

Adjuvant intensity modulated whole-abdominal radiation therapy for high-risk patients with ovarian cancer FIGO stage III: final results of a prospective phase 2 study

BackgroundTo assess late toxicity, quality of life and oncological outcome after consolidative whole abdominal radiotherapy (WART) following cytoreductive surgery and carboplatin/paclitaxel chemotherapy in high risk patients with advanced ovarian cancer FIGO stage III using IMRT (Intensity modulated radiation therapy).MethodsThe OVAR-IMRT-02 study is a multi-center single-arm phase-II-trial. Twenty patients with optimally debulked ovarian cancer stage FIGO III with complete remission after chemotherapy were treated with intensity modulated WART. A total dose of 30 Gy in 20 fractions was applied to the entire peritoneal cavity. Primary endpoint was treatment tolerability; secondary objectives were acute and chronic toxicities, quality of life, rates of therapy disruption/abortion, progression-free survival (PFS) and overall survival (OS).ResultsAll patients completed treatment and 10/20 patients (50%) reached the final study follow-up of 36 months. Late side effects consisted of °1-°2 lower limb edema (44.5%), with one patient (5.6%) showing °3 edema. Three patients (16.7%) showed elevated gamma-Glutamyltransferase. There were no severe late side effects regarding renal or hepatic function or any gastrointestinal toxicity greater than °2. During WART, mean global health status decreased by 18.1 points (95%-CI: 7.1–29.0), but completely normalized after 6 months. The same trend was observed for the function scale scores. Kaplan-Meier-estimated 1-, 2- and 3-year PFS was 74, 51 and 40%, respectively. 1-, 2- and 3-year OS was 89, 83 and 83%, respectively.ConclusionsIntensity modulated WART after aggressive surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute and late toxicity and minor impact on long-term quality of life. Together with the promising results for PFS and OS, intensity modulated WART could offer a new therapeutic option for consolidation treatment of patients with advanced ovarian cancer.Trial registrationThe study is registered with ClinicalTrials.gov (NCT01180504). Registered 12 August 2010 – retrospectively registered.

Inflammatory Bowel Disease in Children with Elevated Serum Gamma Glutamyltransferase Levels

To assess the characteristics of inflammatory bowel disease and disease prognosis among children with elevated gamma glutamyltransferase (GGT) and primary sclerosing cholangitis (PSC)-ulcerative colitis (UC). Our longitudinal, population-based cohort comprised all children and young adults diagnosed with UC in the Canadian province of Manitoba between 2011 and 2018. Diagnosis of PSC was confirmed based on a combination of cholestatic biochemical markers and cholangiographic features. The Fisher exact test with Bonferroni correction was used to examine the relationship between categorical variables. We enrolled 95 children with UC/Inflammatory bowel disease-unclassified with a median age at diagnosis of 14years (IQR: 10.4-15.9years) and 1399 person-years follow-up. Among them, 9 children developed PSC-UC, with an incidence rate of 6.43 new cases per 1000 person-years. In this cohort, 8 (72.7%) of 11 children with high baseline serum GGT levels developed PSC-UC in comparison with 1 (1.2%) of 84 children with normal serum GGT levels at baseline (P<.001). All children with high serum GGT levels at diagnosis had pancolitis in comparison with 63.9% of children with normal serum GGT levels (P=.01). Children with high serum GGT levels were more likely to be perinuclear neutrophil antibodies-positive than those with normal levels (90.9% vs 52.0%, P=.01). Our findings indicated that pediatric patients with UC and with even mild elevations of serum GGT levels, especially at baseline, might be predisposed to develop PSC.

Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2

To investigate the potential role of alcohol use disorder (AUD) in aging processes, we employed Levine’s epigenetic clock (DNAm PhenoAge) to estimate DNA methylation age in 331 individuals with AUD and 201 healthy controls (HC). We evaluated the effects of heavy, chronic alcohol consumption on epigenetic age acceleration (EAA) using clinical biomarkers, including liver function test enzymes (LFTs) and clinical measures. To characterize potential underlying genetic variation contributing to EAA in AUD, we performed genome-wide association studies (GWAS) on EAA, including pathway analyses. We followed up on relevant top findings with in silico expression quantitative trait loci (eQTL) analyses for biological function using the BRAINEAC database. There was a 2.22-year age acceleration in AUD compared to controls after adjusting for gender and blood cell composition (p = 1.85 × 10−5). This association remained significant after adjusting for race, body mass index, and smoking status (1.38 years, p = 0.02). Secondary analyses showed more pronounced EAA in individuals with more severe AUD-associated phenotypes, including elevated gamma-glutamyl transferase (GGT) and alanine aminotransferase (ALT), and higher number of heavy drinking days (all ps < 0.05). The genome-wide meta-analysis of EAA in AUD revealed a significant single nucleotide polymorphism (SNP), rs916264 (p = 5.43 × 10−8), in apolipoprotein L2 (APOL2) at the genome-wide level. The minor allele A of rs916264 was associated with EAA and with increased mRNA expression in hippocampus (p = 0.0015). Our data demonstrate EAA in AUD and suggest that disease severity further accelerates epigenetic aging. EAA was associated with genetic variation in APOL2, suggesting potential novel biological mechanisms for age acceleration in AUD.

Sex differences in the association between perfluoroalkyl acids and liver function in US adolescents: Analyses of NHANES 2013–2016

Perfluoroalkyl acids (PFAAs) are persistent in the environment, highly bio-accumulative in the body, and likely hepatotoxic in humans. There is evidence of sex-specific physiological responses to PFAA exposure. However, epidemiological studies seldom stratify the analyses by sex. Given the high prevalence of liver disease in general population adolescents, this study was designed to determine whether or not there is association between exposure to PFAAs and biomarkers of liver function in adolescent participants of the 2013–2016 National Health and Nutrition Examination Survey, and whether or not such association is sex-specific. Multivariate linear regressions were performed to examine the association between single PFAAs [perfluorooctane sulfonic acid (PFOS); linear form of perfluorooctanoic acid (PFOA); perfluorohexane sulfonic acid (PFHxS); perfluorononanoic acid (PFNA)], and biomarkers of liver function — gamma glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin. Multivariate logistic regressions were performed to estimate adjusted odd ratios (aOR) of elevated ALT, AST and GGT. The study results show that, in females, there was a positive association of the highest PFOA quartile with increased ALT, AST and GGT, and the highest PFNA quartile with increased ALT and AST. Conversely, in male adolescents there was an association of the highest linear PFOA quartile with decreased ALT, and the highest PFNA quartile with ALT and AST. Females had higher odds of clinically-defined elevated ALT with increased PFOA (aOR = 1.79; 95% CI: 1.05, 3.04) or PFNA (aOR = 2.28; 95% CI: 1.08, 2.28), whereas males had decreased odds of clinically-defined elevated ALT with increased n-PFOA (aOR = 0.43; 95% CI: 0.20, 0.93) or PFNA (aOR = 0.5; 95% CI: 0.28, 0.89). In conclusion, there were sex differences in the association between serum PFAA levels and biomarkers of liver function. These results may provide support for analyzing sex-based adverse effects of PFAAs.

Phase 1 Open-Label, Multicenter Study of First-in-Class RORγ Agonist LYC-55716 (Cintirorgon): Safety, Tolerability, and Preliminary Evidence of Antitumor Activity

Transcription factor retinoic acid receptor-related orphan receptor γ (RORγ) regulates type 17 effector T-cell differentiation and function and is key to immune cell regulation. Synthetic RORγ agonists modulate immune cell gene expression to increase effector T-cell activity and decrease immune suppression. A phase 1 study evaluated the safety and tolerability of LYC-55716 (cintirorgon), a first-in-class, oral, small-molecule RORγ agonist in adults with relapsed/refractory metastatic cancer. Patients received 28-day treatment cycles of oral LYC-55716; dose and dosing regimen were determined according to pharmacokinetic profile and safety. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective tumor response rate. No dose-limiting toxicities occurred among the 32 enrolled patients who received LYC-55716 150 mg BID to 450 mg BID. Treatment-related adverse events (AE) were primarily grade 1-2 and included diarrhea (n = 11), fatigue (n = 7), anemia (n = 4), decreased appetite (n = 4), and nausea (n = 4). Grade 3 AEs were anemia (n = 2), elevated gamma-glutamyl transferase (n = 1), and hypophosphatemia (n = 1). Pharmacokinetic concentrations achieved levels expected for target gene regulation. Pharmacodynamic results indicated RORγ pathway engagement. Two patients (NSCLC and sarcomatoid breast cancer) had confirmed partial responses; 11 had disease stabilization for 2 to 12 months (6 received >4 months of treatment). These data support the safety and tolerability of LYC-55716 and selection of 450 mg BID dose for a phase 2a study assessing LYC-55716 clinical activity, safety, and biomarkers in patients with NSCLC, head and neck, gastroesophageal, renal cell, urothelial, and ovarian cancers.

Suboptimal sleep duration and circadian phenotype in adult women residents of Valencia, Venezuela, treated in health campaigns: an associated cardiometabolic profile

Objective: To evaluate the sleep duration, the circadian phenotypes, and their association with sociodemographic and clinical variables, lifestyle, and indicators of cardiometabolic risk in adult women. Materials and methods: A cross-sectional study of 108 adult women living in the city of Valencia, Venezuela, who were treated in health campaigns. Sociodemographic and clinical variables, lifestyle, self-reported sleep duration during weekdays and weekends, and weighted sleep duration (short: 9 hours) were determined. The circadian phenotype or chronotype were assessed by the reduced Horne & Ostberg’s morningness-eveningness questionnaire. Blood pressure, weight, height, waist circumference, and blood biomarkers were measured. Three (3) cardiometabolic status scores were calculated. Hypertension (HTN) and metabolic syndrome (MS) were established. Results: Twenty one point three percent (21.3 %) of the study population presented a short weighted sleep duration and 16.7 % presented a long one. Twenty-eight point seven percent (28.7 %) showed a clearly morning chronotype, 38 % showed a moderately morning chronotype, 32.4 % showed no definite chronotype, 0.9 % showed a moderately evening chronotype, and there were no cases of clearly evening chronotype. Short sleep duration and morning chronotypes were more frequent in women > 40 years. The sleep duration was associated with marital status, occupation and ex-smoker status. The chronotypes were associated with postmenopause. The short sleep duration was associated with abdominal obesity and HTN, and elevation of gamma-glutamyltransferase and uric acid. The long sleep duration was associated with higher glycemia and transaminases. The clearly morning chronotype was associated with HTN, MS and presence of a number of MS components. The short sleep duration and the clearly morning chronotype predicted a high cardiometabolic risk. This association disappeared by adjusting the age and postmenopause status. Conclusions: The suboptimal sleep duration and the circadian phenotypes were associated with sociodemographic, clinical and cardiometabolic risk variables. The short sleep duration and the clearly morning chronotype predicted a high cardiometabolic risk.