Serum Γ-glutamyltransferase Levels Research Articles

Correlation of Liver Enzymes and Serum Ferritin in Patients With β-Thalassaemia Major

Background: β-Thalassemia major is a hereditary hematological disorder that necessitates regular blood transfusions, leading to iron overload and subsequent liver injury. Elevated serum liver enzymes and ferritin are commonly used to monitor liver function in these patients; however, their reliability in predicting true hepatic dysfunction remains unclear. Objective: To determine the sensitivity, specificity, and diagnostic accuracy of serum liver enzymes and ferritin in predicting liver dysfunction, with hypoalbuminemia as the gold standard, in pediatric patients with β-thalassemia major. Methods: This cross-sectional validation study was conducted at the Department of Paediatrics, Combined Military Hospital, Rawalpindi, from July 2022 to February 2024. A total of 75 pediatric patients with β-thalassemia major were included using consecutive non-probability sampling. Patients with concurrent liver diseases, metabolic disorders, or conditions that could alter liver enzyme levels were excluded. Blood samples were collected to measure serum Alanine Transaminase (ALT), Aspartate Transaminase (AST), γ-Glutamyltransferase (γ-GT), ferritin, and albumin levels. Hypoalbuminemia was defined as a serum albumin level <3.5 g/L. The diagnostic accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of ALT, AST, γ-GT, and ferritin in predicting hypoalbuminemia were calculated using 2×2 contingency tables. Data were analyzed using SPSS version 25. Results: Among the 75 patients, 18 (24.0%) exhibited hypoalbuminemia. The sensitivity, specificity, and diagnostic accuracy of ALT in detecting hypoalbuminemia were 83.33%, 31.58%, and 44.00%, respectively. For AST, these values were 50.00%, 29.82%, and 34.67%, respectively. γ-GT showed a sensitivity of 83.33%, specificity of 14.04%, and diagnostic accuracy of 30.67%. Ferritin had a sensitivity of 83.33%, specificity of 19.30%, and diagnostic accuracy of 34.67%. None of the markers showed satisfactory predictive value for hypoalbuminemia. There was a partial correlation between hyperferritinemia and elevated liver enzymes, with γ-GT showing the highest sensitivity (91.80%) and diagnostic accuracy (82.67%). Conclusion: Serum liver enzymes and ferritin are not reliable markers for predicting liver dysfunction as indicated by hypoalbuminemia in pediatric patients with β-thalassemia major. These findings suggest that additional clinical assessments and more specific biomarkers are necessary for accurate evaluation of liver health in this population.

Serum γ-glutamyltransferase levels and obesity status changes the risk of prehypertension in Chinese adults

ObjectiveIt’s well known that γ-Glutamyltransferase (γ-GGT) and obesity plays an important role in the development of preHT. However, the effect of γ-GGT on preHT in populations with different obesity status remains unclear. MethodsFrom February 2014 to January 2018, a total of 20,368 participants were enrolled in this study after excluding those with hypertension and liver diseases. Fasting blood samples were collected to measure γ-GGT and blood lipid levels and glucose indices. Demographic andclinical parameters such assex, age, height, weight, neck circumference (NC), waist circumference (WC), hip circumference (HC), and body fat ratio (BFR); and information on smoking and alcohol consumption were collected by trained medical professionals. ResultsParticipants were divided into three groups based on obesity status. The prevalence of preHT was 83.5 % in the obesity group was higher than that in the overweight group (58.9 %) and the normal group (47.1 %). γ-GGT in different categories of obesity indices were significantly different, and higher obesity indices were found with higher γ-GGT levels. The interaction of γ-GGT and obesity indices such as NC, WC, HC, and BFR on the prevalence of preHT was significant (P = 0.028, 0.002, 0.007, and 0.034, respectively). Serum γ-GGT was found to be positively associated with preHT in participants with normal and overweight body mass indices. ConclusionOur results indicate that γ-GGT is a risk factor for preHT in participants who are nonobese, and that the obesity indices NC, WC, HC, BFR, and γ-GGT were contributing factors in increasing the risk of preHT.

Liver Involvement is Associated with Higher Risk of Rapidly Progressive Interstitial Lung Disease and Mortality in Anti-Melanoma Differentiation-Associated Gene 5 Antibody- Positive Dermatomyositis.

This study aimed to assess liver involvement and investigate its correlation with rapidly progressive interstitial lung disease (RP-ILD) and mortality in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5 positive) DM patients. This retrospective study included 159 patients diagnosed with anti-MDA5 positive DM or anti-synthetase syndrome (ASyS). Clinical features and laboratory findings were compared between patients with anti-MDA5 positive DM and patients with ASyS. In the anti-MDA5 positive DM cohort, clinical features and laboratory findings between patients with liver involvement and without liver involvement were further compared. The effects of liver involvement on the overall survival (OS) and development of RP-ILD were also analyzed using Kaplan-Meier method and Cox regression analysis. Levels of serum aspartate aminotransferase (AST), alanine transaminase (ALT), γ-glutamyl transferase (γGT) and alkaline phosphatase (ALP) were all significantly higher in patients with anti-MDA5 positive DM than those in patients with ASyS. In our cohort of anti-MDA5 positive DM patents, 31 patients (34.4%) were complicated with liver involvement. Survival analysis revealed that serum ferritin >1030.0 ng/mL (p<0.001), ALT >103.0 U/l (p<0.001), AST >49.0 U/l (p<0.001), γGT >82.0 U/l (p<0.001), ALP >133.0 U/l (p<0.001), lactate dehydrogenase (LDH)>474.0 U/l (p<0.001), plasma albumin (ALB) <35.7 g/l (p<0.001) and direct bilirubin (DBIL) >2.80 μmol/l (p=0.002) predicted poor prognosis. The incidence of RP-ILD increased remarkably in patients with liver involvement compared to patients without liver involvement (58.1% vs 22.0%, p=0.001). Multivariate analysis revealed that elevated serum ALT level was an independent risk factor for mortality (HR 6.0, 95% CI 2.3, 16.2, p<0.001) and RP-ILD (HR 5.9, 95% CI 2.2, 15.9, p<0.001) in anti-MDA5 positive DM patents. Liver involvement is common in patients with anti-MDA5 positive DM. Elevated serum ALT level was an independent risk factor for RP-ILD and mortality in patients with anti-MDA5 positive DM.

Study of Association of Chromosomal Region 1Q21-23 with Rheumatoid Arthritis and Their Correlation with Severity of Disease.

The understanding of the pathophysiology of rheumatoid arthritis (RA) has taken a major step forward with the research of new illness-related genes and further deciphering the involved molecular. Gene variants like human leukocyte antigen (HLA)-DRB1 and PTPN22 1858T act as individual risk factors for RA. It also serves as a risk factor for the rate of progression of joint destruction and clinical manifestations in autoimmune diseases like RA. The focus of this study is to find out the association of chromosomal region 1q21-23 with RA and its connection with disease severity using the disease activity score (DAS) and distribution frequency of the prevalent alleles of such genes in an already recruited group of patients/controls of India, specifically Northwest Rajasthan. This was a case-control study wherein every patient of RA aged 16 years and above diagnosed with RA as per the 2010 American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) revised criteria for RA in Outpatient Department (OPD) and Inpatient Department (IPD) patients were included. Blood samples of the study population were drawn at Sardar Patel Medical College (SPMC), Bikaner (rheumatology OPD), along with the cooperation of Birla Institute of Technology and Science (BITS), Hyderabad (Department of Biological Sciences) from July 2009 to January 2012. A total of 100 controls (without any previous history of disease) and 135 cases were selected considering inclusion and exclusion criteria. Clinical data along with laboratory parameters like complete blood count, serum electrolytes (sodium, potassium, calcium, and chlorine ions), blood sugar, blood urea with serum creatinine, lactate dehydrogenase (LDH) isoenzymes assay, serum glutamic-oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT) ratio, serum γ-glutamyl transferase (GGT) level, serum amylase, arterial blood gas (ABG), total serum proteins were evaluated and recorded from the patients. Our study showed control group has a mean age of 45.11 + 4.12 years. The case and control groups did not have significant differences in any of the clinical variables. 59% of cases show joint deformity. Allelic frequencies of the D1S498 polymorphism in cases were found significant in sizes 198, 204, 208, and 210, while it was found insignificant in sizes 192, 196, 200, 202, and 206. No correlation was found in allelic frequencies of the D1S318 polymorphism in cases and controls. Bigger cohort studies will allow better genomic elucidation of clinically defined intermediate phenotypes evaluated in RA patients by virtue of the autoimmune origin of the disease and its diverse symptoms in patients. Genetic-molecular studies can be a milestone for adopting effective personalized treatment for such progressively debilitating diseases. How to cite this article: Gauri LA, Meena MK, Singh U, et al. Study of Association of Chromosomal Region 1Q21-23 with Rheumatoid Arthritis and Their Correlation with Severity of Disease. J Assoc Physicians India 2023;71(9):28-32.

Association between the accumulation of elevated serum γ-glutamyltransferase level and risk of atrial fibrillation: a nationwide cohort study

Atrial fibrillation (AF) is the most common cardiac arrhythmia. The association between AF and γ-Glutamyltransferase (GGT) was not fully established. This study demonstrated the independent association of cumulative GGT score and AF incidence with the dose-response relationship. Using the Korean National Health Insurance Corporation database, adult subjects who had 4 consecutive annual health examinations from 2009 to 2012 were enrolled. A cumulative GGT score was calculated as the cumulative number of the highest GGT quartile amongst four examinations (0–4 times). A multivariable Cox proportional hazards regression analysis was performed. Among a total of 3,500,847 people included, AF was developed in 27,752 people (0.793%) during a median of 8.0 years of follow up. The incidence rate of AF and adjusted hazard ratio were increased by a stepwise manner in the higher quartile group and cumulative GGT score group. In subgroup analysis, this trend was more prominent in the elderly, people without hypertension, non-obese people, and people without any four comorbidities (diabetes mellitus, hypertension, dyslipidemia, and obesity). Our results suggest multiple accumulation of elevated GGT levels in health examination might be a useful marker for risk stratification of AF development, especially in the elderly and healthy population.

Serum γ-glutamyltransferase level and incidence risk of metabolic syndrome in community dwelling adults: longitudinal findings over 12 years

PurposeAlthough a recent meta-analysis demonstrated a positive association between serum γ-glutamyltransferase (GGT) and metabolic syndrome (MetS), sex differences in the relationship between GGT levels and MetS risk were not fully considered. We prospectively examined the relationship between serum GGT levels and incidence risk of MetS.MethodsData were collected from the Korean Genome and Epidemiology Study (KoGES) enrolled in 2001–2002. Among 10,030 total participants, 5960 adults (3130 men and 2830 women) aged 40–69 without MetS were included and divided according to sex-specific quartiles of baseline serum GGT levels and followed up biennially until 2014. The hazard ratios (HRs) with 95% confidence intervals (CIs) for incident MetS were prospectively analyzed using multiple Cox proportional hazards regression analysis models.ResultsAmong 5960 participants, 1215 males (38.8%) and 1263 females (44.6%) developed MetS during 12-year follow up. Higher quartiles of GGT showed significantly higher cumulative incidence of MetS in both sexes (log-rank test P < 0.001). The HRs (95% CIs) for incident type 2 diabetes for the highest quartile versus referent lowest quartile for serum GGT levels were 3.01 (2.35–3.76) for men and 1.83 (1.30–2.57) for women after adjusting for age, smoking status, daily alcohol intake (g/day), regular exercise, family history of diabetes, and log-transformed LDL-cholesterol, creatinine, and aminotransferase levels.ConclusionIn conclusion, high levels of GGT were found to be associated with increased risk of Mets in both men and women and the positive associations were stronger in men than in women.

Taraxasterol alleviates aflatoxin B1-induced liver damage in broiler chickens via regulation of oxidative stress, apoptosis and autophagy

Aflatoxin B1 (AFB1) is the most dangerous and abundant mycotoxin, which is toxic to almost all animals, and poultry is more sensitive to AFB1 toxicity. Ingesting AFB1-contaminated feed can cause significant liver damage and brings serious harm to poultry, which greatly restricts the development of the poultry industry. The present research was implemented to explore the intervention effect and its mechanism of taraxasterol on liver damage induced by AFB1 in broiler chickens. The liver damage model in broiler chickens was established by feeding 0.5 mg/kg AFB1 feed, and taraxasterol (25, 50 and 100 mg/kg BW, respectively) was given in the drinking water for 21 days. The growth performance, liver function, oxidative stress, apoptosis and autophagy were evaluated. The results showed that taraxasterol increased BW and reduced feed-to-gain ratio of broiler chickens induced by AFB1. Taraxasterol improved the levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), total bilirubin (TBIL) and alkaline phosphatase (ALP), and attenuated hepatic histopathological changes induced by AFB1. Meantime, taraxasterol down-regulated cytochrome P450 (CYP450) enzyme system CYP1A1 and CYP2A6 mRNA expression, inhibited the overproduction of reactive oxygen species (ROS) and malondialdehyde (MDA), and enhanced the activities of antioxidant enzymes glutathione (GSH) and catalase (CAT) and the content of antioxidant superoxide dismutase (SOD) of the liver in broiler chickens induced by AFB1. Furthermore, taraxasterol up-regulated the mRNA and protein expression of hepatic nuclear factor E2 related factor 2 (Nrf2), heme oxygenase 1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1), and down-regulated the expression of hepatic kelch like ECH associated protein 1 (Keap1) induced by AFB1 in Keap1/Nrf2 signaling pathway. The ultrastructural observation and RT-qPCR results found that taraxasterol inhibited apoptosis of hepatocytes, up-regulated the expression of B-cell lymphoma-2 (Bcl-2) mRNA and down-regulated the expression of Bax and caspase3 mRNA. Further, taraxasterol restored the autophagy of hepatocytes and down-regulated the mRNA expression of phosphatidylinositol 3-kinase K (PI3K), protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in AFB1-induced liver of broiler chickens. The above results indicate that taraxasterol alleviates liver damage induced by AFB1 in broiler chickens through regulation of Keap1/Nrf2 signaling pathway to exert its antioxidant effect, mitochondrial apoptosis pathway to improve anti-apoptotic ability and PI3K/AKT/mTOR pathway to restore autophagy.

Assessment of Treatment Patterns in Patients with Alcohol Withdrawal Syndrome during Hospitalisation and Post-discharge: A Retrospective Cohort Study

Introduction: Alcohol dependence is an increasing and pervasive problem. Alcohol Withdrawal Syndrome (AWS) is a cluster of symptoms that occur in alcohol-dependent individuals after cessation or reduction of alcohol consumption. However, studies on the clinicoepidemiological profile of patients with AWS and treatment patterns in India are scarce. Aim: To assess the treatment patterns during hospitalisation and after discharge in Indian patients with AWS. Materials and Methods: A retrospective observational study was conducted using data from 1000 patients with AWS who were admitted to nine addiction centres across India. Data from medical charts from the previous five years were collected over six months, from January to June 2022. The study included patients of either sex, aged ≥18 years at the time of data collection, who had been hospitalised for AWS symptoms and had ≥3 months of documented follow-ups. The primary endpoints of the study were the most commonly used medications and their dose titrations in the treatment of AWS, as well as the duration of treatment in the hospital and post-discharge. Key secondary endpoints included the socio-demographic profile of patients, common comorbidities, common signs and symptoms, the association between prescription patterns of Benzodiazepines (BZDs) and liver enzyme levels, and the average duration of hospital stay. Continuous variables were summarised as mean and Standard Deviation (SD), while categorical variables were summarised as frequency and percentages. Levels of serum Aspartate Aminotransferase (AST), Alanine Transaminase (ALT), γ-Glutamyl Transferase (GGT), and bilirubin were recorded from the source data, if available, and the association with the use of chlordiazepoxide and lorazepam was analysed using the Chi-square test. Results: The mean±SD age of the 1000 enrolled patients was 41.4±9.6 years, with the majority (n=997; 99.7%) being males. BZDs were the mainstay pharmacotherapy, with lorazepam (n=686; 68.6%) and chlordiazepoxide (n=482; 48.2%) being the two most commonly prescribed BZDs during hospitalisation. During post-discharge treatment, 57.0% (n/N=74/130) of patients received lorazepam, while 52.0% (n/N=67/130) received chlordiazepoxide. Frequently used drug regimens during hospitalisation included fixed doses of chlordiazepoxide {25 mg twice a day (BID:143/482; 29.7%), 20 mg thrice a day (TID:103/482; 21.4%), or 25mg TID (87/482; 18.0%)}, or lorazepam {2 mg TID (188/686; 27.4%), 2 mg BID (183/686; 26.7%), or 2 mg once a day (OD;175/686; 25.5%)}. Commonly observed signs and symptoms included tremors (n=567; 56.7%), irritability (n=539; 53.9%), and agitation (n=500; 50.0%). Depression (n=182; 18.2%) and anxiety (n=136; 13.6%) were the most commonly reported co-morbidities. Among the patients, only 13.4% (86/641) had an AST/ALT ratio &gt;2, and 12.9% (44/340) had AST and GGT levels &gt;2× Upper Limit of Normal (ULN). There was no significant difference in these patients between those receiving and not receiving chlordiazepoxide (p&gt;0.05). The mean±SD duration of hospitalisation was 23.1±18.97 days, while the mean±SD duration of treatment during hospitalisation and post-discharge was 22.3±16.36 days and 71.6±52.3 days, respectively. Conclusion: The two most commonly prescribed drugs during hospitalisation and post-discharge were the BZDs, lorazepam and chlordiazepoxide. Fixed-dose regimens of chlordiazepoxide at 25 mg BID or TID, or 20 mg TID, and lorazepam at 2 mg TID, BID, or OD were frequently used during hospitalisation.

Case series of progressive familial intrahepatic cholestasis type 3: Characterization of variants in ABCB4 in China.

To improve the accuracy of the diagnosis of familial progressive intrahepatic cholestasis type 3 (PFIC3, https://www.omim.org/entry/602347). Between September 2019 and March 2021, we recruited four patients with PFIC3 from two liver centers in East China. Molecular genetic findings of ATP-binding cassette subfamily B member 4 [ATP binding cassette transporter A4 (ABCB4), https://www.omim.org/entry/171060] were prospectively examined, and clinical records, laboratory readouts, and macroscopic and microscopic appearances of the liver were analyzed. Four patients experienced cholestasis, mild jaundice, and elevated levels of serum direct bilirubin, γ-glutamyltransferase, or total bile acids. All patients had moderate-to-severe liver fibrosis or biliary cirrhosis, and their liver biopsy specimens stained positive with rhodamine. Molecular immunohistochemistry revealed reduced or absent MDR3 expression in all liver specimens. A novel mutation of ABCB4 (c.1560 + 2T > A) was identified in patients with PFIC3, which is of high clinical significance and may help understand mutant ABCB4 pathogenesis. MDR3 immunohistochemistry and molecular genetic analyses of ABCB4 are essential for the accurate diagnosis of PFIC3.

Association of Serum γ-Glutamyltransferase With C-Reactive Protein Levels in Patients With Coronary Heart Disease.

Serum γ-glutamyltransferase (GGT) levels have been shown to be associated with C-reactive protein (CRP) levels. Nevertheless, studies on this relationship in coronary heart disease (CHD) populations are limited. This study retrospectively assessed 17523 patients with CHD undergoing GGT and CRP testing. They were divided into 3 groups according to GGT tertiles. The critical points for high CRP levels was 10.0mg/L, which corresponded to the 75th percentile. Logistic regression analysis was used to analyze the association between GGT and CRP levels in CHD patients. The baseline analysis showed significant differences in related parameters among patients with CHD. Compared with GGT tertile 1 (T1), the odds ratio (OR) of T3 for GGT in CHD patients was 2.15 (95% confidence interval [CI]: 1.96-2.36). The association between GGT and CRP was higher in males (OR: 2.23; 95% CI: 1.98-2.52) than in females (OR: 2.18; 95% CI: 1.89-2.51). This study showed an association between serum GGT and CRP levels in patients with CHD. GGT may be an inflammatory marker and an additional measure for assessing cardiovascular risk.

Development of a Prognostic Nomogram in Hepatocellular Carcinoma with Portal Vein Tumor Thrombus Following Trans-Arterial Chemoembolization with Drug-Eluting Beads.

ObjectiveTo develop and validate a prognostic nomogram in eastern patients with hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) receiving trans-arterial chemoembolization with drug-eluting beads (DEB-TACE).MethodsThis retrospective study included 200 patients with training cohort (n = 118) from institution 1 and test cohort (n = 82) from institution 2. All these patients received first-line DEB-TACE between October 2016 and October 2018. Multivariate Cox proportional hazard regression analysis was performed on the training cohort to reveal the independent prognostic factors, and then prognostic nomograms were developed. In order to evaluate the performance of the nomogram comprehensively in both the training and test cohorts, C-index, Kaplan–Meier curve with Log rank test, receiver operating characteristic curve (ROC), calibration plot, and decision curve analysis (DCA) were performed.ResultsTumor number, serum γ-glutamyl transferase (GGT) level, and level of PVTT were independent risk factors of prognosis. A nomogram was constructed to predict 6-, 12- and 18-month overall survival (OS) based on these identified prognostic factors. C-indexes of the nomogram were 0.88 (95% confidence interval [CI], 0.79–0.97) in the training cohort and 0.87 (95% CI, 0.75–0.99) in the test cohort. The Kaplan–Meier curve analysis showed that the nomogram was able to separate patients into low- and high-risk subgroups. ROC curves for the nomogram at 6-, 12- and 18-month showed satisfied discrimination, with an AUC of 0.765, 0.803 and 0.809 in the training cohort, respectively, and 0.772, 0.724 and 0.746 in the test cohort, respectively. The calibration curve demonstrated good agreement between predicted and actual survival rates in the training and test cohorts. The decision curve showed good performance of the nomogram in terms of clinical application.ConclusionWe developed and validated a nomogram that was accurate and clinically useful in eastern patients with HBV-associated HCC with PVTT who underwent DEB-TACE.

Endoscopic Biliary Decompression by Dual Stents in Elderly Patients with Acute Cholangitis of Severe Type Due to Choledocholithiasis.

Background/Aims: Both endoscopic nasobiliary drainage (ENBD) and a plastic stent placement have some limitations in biliary decompression of elderly patients with acute cholangitis of severe type (ACST) due to choledocholithiasis. Dual stent placement may improve bile drainage without obvious discomfort. Here, we evaluated its advantages in the biliary decompression of elderly patients with ACST. Materials and Methods: A total of 257 elderly patients (≥65 years) with ACST had undergone urgent endoscopic decompression by nasobiliary catheter (ENBD group), single plastic stent (single-stent group), or dual plastic stents (dual-stent group). The data of the three groups was compared retrospectively. Results: The demographic data of the patients in the three groups were comparable. After endoscopic decompression, the serum total bilirubin and γ-glutamyl transferase levels in the dual-stent group were decreased faster than that in the single-stent group (P < .05). The abdominal pain in the dual-stent group was dramatically slighter than that in the ENBD group (P < .05). Compared with two other groups, the acute physiology and chronic health evaluation II scores were decreased dramatically quicker (P < .05) and the length of intensive care unit stay was significantly shorter (P < .05) in the dual-stent group. In the second endoscopic retrograde cholangiopancreatography, the rate of complete stone clearance in the dual-stent group was significantly higher than that in the ENBD group (P < .05). Conclusions: Dual-stent placement might be a better choice for elderly patients with ACST due to choledocholithiasis in comparison with ENBD or a single-stent placement.

Deleterious Variants in ABCC12 are Detected in Idiopathic Chronic Cholestasis and Cause Intrahepatic Bile Duct Loss in Model Organisms

The etiology of cholestasis remains unknown in many children. We surveyed the genome of children with chronic cholestasis for variants in genes not previously associated with liver disease and validated their biological relevance in zebrafish and murine models. Whole-exome (n= 4) and candidate gene sequencing (n= 89) was completed on 93 children with cholestasis and normal serum γ-glutamyl transferase (GGT) levels without pathogenic variants in genes known to cause low GGT cholestasis such as ABCB11 or ATP8B1. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 genome editing was used to induce frameshift pathogenic variants in the candidate gene in zebrafish and mice. In a 1-year-old female patient with normal GGT cholestasis and bile duct paucity, we identified a homozygous truncating pathogenic variant (c.198delA, p.Gly67Alafs∗6) in the ABCC12 gene (NM_033226). Five additional rare ABCC12 variants, including a pathogenic one, were detected in our cohort. ABCC12 encodes multidrug resistance-associated protein 9 (MRP9) that belongs to the adenosine 5'-triphosphate-binding cassette transporter C family with unknown function and no previous implication in liver disease. Immunohistochemistry and Western blotting revealed conserved MRP9 protein expression in the bile ducts in human, mouse, and zebrafish. Zebrafish abcc12-null mutants were prone to cholangiocyte apoptosis, which caused progressive bile duct loss during the juvenile stage. MRP9-deficient mice had fewer well-formed interlobular bile ducts and higher serum alkaline phosphatase levels compared with wild-type mice. They exhibited aggravated cholangiocyte apoptosis, hyperbilirubinemia, and liver fibrosis upon cholic acid challenge. Our work connects MRP9 with bile duct homeostasis and cholestatic liver disease for the first time. It identifies a potential therapeutic target to attenuate bile acid-induced cholangiocyte injury.

Establishment of age- and sex-specific reference intervals for serum liver function tests in pediatric population aged 1-

BackgroundThe diagnosis, treatment, and prognosis of pediatric diseases rely on the accurate establishment of the reference interval (RI). This study aimed to establish pediatric RIs for liver function tests and evaluated the correlation of the analytes.MethodsPediatric population (aged 1–<18 years) was prospectively recruited in Jilin Province, China. Analytes detected by Ortho VITORS 5600 automatic biochemical analyzer. All strata were divided using the regression tree and Harris and Boyd's method. The dynamic changes of RI were evaluated by the lambda‐mu‐sigma method.ResultsReference individuals were comprised of 6,322 children and adolescents. Age and sex differences were present in all analytes except serum total protein. The serum albumin, total protein, γ‐glutamyl transferase, total bilirubin, and unconjugated bilirubin levels increased with age while serum aspartate aminotransferase was opposite. The serum alanine aminotransferase level reached a trough at the age of 5 and later steadily in males but slowly decreased in females. The serum alkaline phosphatase level dropped rapidly after reaching a peak at 9 years old in females and 12 years old in males. RIs were divided into 11 partitions at most and 5 partitions at least. The strongest correlation between analytes was total bilirubin and unconjugated bilirubin (r = 0.788), followed by total bilirubin and albumin (r = 0.511).ConclusionsAnalytes show unique dynamic changes in pediatric population. The correlations among liver function tests can inform future studies of particular variables. Age‐ and sex‐special pediatric RIs should be established to help an accurate diagnosis of disease.

Association between routine biomarkers and atrial fibrillation in patients undergoing implantation of a dual-chamber pacemaker.

BackgroundElderly patients having a permanent pacemaker frequently have atrial remodeling. We examined the association between routine biomarkers and atrial fibrillation (AF) in patients receiving a dual‐chamber pacemaker for sinus node disease (SND) or second‐/third‐degree atrioventricular block.MethodsWe recorded clinical, laboratory, and electrocardiographic parameters as well as pacemaker lead parameters at implantation. The final analysis included 217 patients with SND and 393 patients with atrioventricular block. Notably, 102/217 (47%) of the SND patients (median age: 77 years, 54% men) and 54/393 (14%) of the atrioventricular block patients (median age: 79 years, 54% men) had AF history (paroxysmal or persistent).ResultsMultivariable analysis showed that red blood cell distribution width (RDW) (OR: 1.17; 95% CI: 1.05‐1.36; P = .05) and serum γ‐glutamyl transferase (γGT) levels (OR: 1.15; 95% CI: 1.03‐1.28; P = .04) were independently associated with AF history in patients with SND. In ROC curve analysis, the area under the curve (AUC) was 0.648; P < .01 for RDW, and 0.753; P < .01 for γGT. A RDW cut‐off point of 14 was associated with AF with a sensitivity of 67% and a specificity of 68%, while a γGT cut‐off point of 21 was associated with AF with a sensitivity of 80% and a specificity of 65%. In patients with second‐/third‐degree atrioventricular block, there were no significant independent correlations between AF and the parameters studied.ConclusionsIn elderly patients with SND, RDW and γGT have an independent association with AF history. Our study failed to show any corresponding associations in patients with advanced disorders of atrioventricular conduction.

Predictive role of γ-glutamyltransferase in patients receiving nivolumab therapy for metastatic renal cell carcinoma.

γ-Glutamyltransferase is reportedly associated with survival in local and metastatic renal cell carcinoma patients; however, its predictive role among patients treated with immune-checkpoint inhibitors are unknown. This study aimed to investigate the role of γ-glutamyltransferase as a predictive marker among metastatic renal cell carcinoma patients undergoing nivolumab therapy. We retrospectively evaluated 69 nivolumab-treated metastatic renal cell carcinoma patients upon failure of one or more systematic therapies. Serum γ-glutamyltransferase levels were determined at baseline and 2months after nivolumab treatment initiation. Patients were classified as high (≥ 49 U/L) and low (< 49mg/dL) from baseline GGT levels and the outcomes were compared between the two groups. Furthermore, increased (after/baseline ≥ 2) and non-increased (after/baseline < 2) groups were compared. Progression-free survival and overall survival were evaluated after nivolumab initiation. Overall survival was significantly shorter in the high baseline γ-glutamyltransferase group (20.3%) than in the low group (79.7%) (median 2.33 vs not reached [months], p = 0.0051). Progression-free survival and the overall survival were significantly shorter in the increased than in the non-increased group (24.6% and 75.4%, respectively) (median PFS: 4.43 vs 7.23 [months], p = 0.0373/OS: 24.00 vs not reached, p = 0.0467). On multivariate analyses, high baseline γ-glutamyltransferase was an independent factor for overall survival (p = 0.0345) and increased γ-glutamyltransferase was an independent factor for progression-free survival (p = 0.0276) and overall survival (p = 0.0160). High baseline γ-glutamyltransferase and its early increase are associated with a poor prognosis in metastatic renal cell carcinoma patients receiving nivolumab. Serum γ-glutamyltransferase levels may help predict treatment outcomes.

Fosravuconazole to treat severe onychomycosis in the elderly.

Fosravuconazole is a novel oral antifungal drug developed in Japan and used to treat tinea unguium since 2018. Its excellent oral absorbability and systemic bioavailability has enabled short-duration therapy of 3months. Furthermore, no concomitant drugs are contraindicated due to the presence of the mild inhibitor of cytochrome P450 enzyme which is responsible for polypharmacy adverse effects. Therefore, it can be safely administrated to elderly patients. Elderly patients (≥65years old) with severe onychomycosis (≥50% nail involvement) were treated with oral fosravuconazole 100mg once daily for 12weeks. The rate of involvement improved from 86.6% to 28.1% (P<0.01). The efficacy (i.e. percentage of those rated as "improved" and better) and cure rate was 83.8% (31/37) and 29.7% (11/37), respectively. Furthermore, when focusing on the thin nail group (<3mm), the efficacy and cure rate was 88.2% (15/17) and 58.8% (10/17), respectively. Although the serum γ-glutamyltransferase levels increased in 21.6% (8/37), all patients recovered without any specific treatments.

γ-Glutamyltranspeptidase as a Prognostic Biomarker in Advanced Hepatocellular Carcinoma Treated with Transarterial Chemoembolization

PurposeTo evaluate the prognostic value of pretreatment serum γ-glutamyltransferase (GGT) level in patients with advanced hepatocellular carcinoma (HCC) receiving transarterial chemoembolization. Materials and MethodsThis retrospective study included 140 patients (123 male, 17 female; mean age, 56.9 y ± 12.0; range, 22.0–82.0 y) with Barcelona Clinic Liver Cancer class C HCC who received first-line conventional chemoembolization between December 2013 and March 2018. Patients were divided into low and high GGT groups based on a cutoff value calculated with a receiver operating characteristic curve. Overall survival (OS) was compared between groups by log-rank test. Univariate and multivariate survival analyses were performed. ResultsThe optimal cutoff values of GGT were 119.5 U/L in men and 175.0 U/L in women. The 6-, 9-, and 12-mo OS rates were 81.7%, 72.4%, and 62.9%, respectively, for patients in the low GGT group (n = 44) and 58.8%, 35.7%, and 28.8%, respectively, for patients in the high GGT group (n = 96; P < .001). Multivariable Cox regression analysis identified high pretreatment serum GGT level (hazard ratio [HR], 2.71; 95% confidence interval [CI], 1.67–4.40; P < .001), multiple tumors (HR, 3.05; 95% CI, 1.23–7.53; P = .02), and performance of target treatment (ie, sorafenib; HR, 0.41; 95% CI, 0.24–0.72; P = .002) or ablation (HR, 0.35; 95% CI, 0.18–0.66; P = .001) as independent prognostic factors for OS. ConclusionsPretreatment serum GGT level was an independent prognostic factor for OS in patients with advanced HCC treated with chemoembolization, suggesting that GGT is a useful prognostic biomarker for advanced HCC.

Hepatoprotective and Antioxidant Capacity of Mallotus repandus Ethyl Acetate Stem Extract against d-Galactosamine-Induced Hepatotoxicity in Rats.

Mallotus repandus (M. repandus) is traditionally used to treat muscle pain, itching, fever, rheumatic arthritis, and a variety of liver disorders. The aim of the present work was to evaluate the hepatoprotective activity and the antioxidant potential of the ethyl acetate stem extract of M. repandus (ESMR) against d-galactosamine (d-GalN)-induced hepatopathy, along with a possible mechanism of action in rats. In vivo hepatoprotective activity of ESMR was examined using d-galactosamine (d-GalN)-induced hepatotoxicity in Sprague–Dawley rats. For this purpose, levels of serum diagnostic markers, activity of hepatic antioxidant enzymes, and liver histo-architecture were employed to assess the protective efficacy of ESMR. Furthermore, the total phenolic, flavonoid, and tannin contents were quantitated, and the antioxidant capacity of the extract was evaluated using different methods such as 2,2′-diphenyl-1-picrylhydrazyl (DPPH), nitric oxide (NO), hydrogen peroxide (H2O2), and hydroxyl radical (OH•) scavenging assays. Intraperitoneal d-GalN injection triggered hepatotoxicity, as shown by the noticeable increase in the serum hepatic marker enzymes, bilirubin content, γ-glutamyl transferase (GGT), total cholesterol (TC), triglycerides (TGs), and malondialdehyde (MDA), whereas glutathione, superoxide dismutase, and catalase levels were significantly lower compared with that of the control. Pretreatment with ESMR reduced the hepatic enzyme levels along with bilirubin, GGT, and MDA compared to the d-GalN-intoxicated group. These results were supported by histopathological studies, where d-galactosamine caused coagulative necrosis, hemorrhage, and inflammation. However, pretreatment with ESMR ameliorated the histo-architectural changes and brought them back to normal. Results also revealed that the total polyphenolic, flavonoid, and tannin content, and total antioxidant capacity of ESMR were 136.30 ± 0.78 mg GAE/g mg, 38.72 ± 0.85 mg QE/g, 75.88 ± 0.54 mg TAE/g, and 123.16 ± 0.24 mg AAE/g, respectively. In addition, ESMR inhibited free radicals with IC50 values of 94.47 ± 0.51, 127.33 ± 0.36, 164.12 ± 0.45, and 254.14 ± 0.35 μg/mL in DPPH, NO, H2O2, and OH• free radical scavenging assays, respectively. These findings highlight the protective role of ESMR against hepatic injury induced by d-GalN, which may be attributed to its higher antioxidant properties, thereby scientifically justifying its traditional use.

Novel Variant ATP8B1 mutation in a child with progressive familial intrahepatic cholestasis (type 1)

Background: Progressive familial intrahepatic cholestasis (PFIC) is a group of heterogeneous autosomal recessive disorders attributed to hepatocellular cholestasis, characterized by low serum γ-glutamyl transferase (GGT) levels due to mutation in ATP8B1. Case Presentation: We present a case of 2-year-old male child who experienced persistent marked pruritus, jaundice, and failure to thrive since 3 months of age. He was diagnosed as PFIC on the basis of histology, biochemical, and clinical finding. On genetic analysis by next generation sequencing, a novel homozygous missense variation in exon 19 of the ATP8B1 gene [chr18:g.55335672C>T; Depth: 71x] resulting in the amino acid substitution of Glutamic acid for Glycine at codon 733 [p.Gly733Glu;ENS0536015.1], which was confirmed by sanger sequencing of parents. Conclusion: We report a case of PFIC type 1 with a novel homozygous missense variation in exon 19 of the ATP8B1 gene with both mother and father as heterozygous carrier. Further confirmation of this variant in ATP8B1 mutation will occur by identification of similar phenotypes with similar mutation.