Hypersensitivity to ferroptosis in chromophobe RCC is mediated by a glutathione metabolic dependency and cystine import via solute carrier family 7 member 11.

Chromophobe (Ch) renal cell carcinoma (RCC) arises from the intercalated cell in the distal nephron. There are no proven treatments for metastatic ChRCC. A distinguishing characteristic of ChRCC is strikingly high levels of reduced (GSH) and oxidized (GSSG) glutathione. Here, we demonstrate that ChRCC-derived cells exhibit higher sensitivity to ferroptotic inducers compared with clear-cell RCC. ChRCC-derived cells are critically dependent on cystine via the cystine/glutamate antiporter xCT to maintain high levels of glutathione, making them sensitive to inhibitors of cystine uptake and cyst(e)inase. Gamma-glutamyl transferase 1 (GGT1), a key enzyme in glutathione homeostasis, is markedly suppressed in ChRCC relative to normal kidney. Importantly, GGT1 overexpression inhibits the proliferation of ChRCC cells in vitro and in vivo, suppresses cystine uptake, and decreases levels of GSH and GSSG. Collectively, these data identify ferroptosis as a metabolic vulnerability in ChRCC, providing a potential avenue for targeted therapy for these distinctive tumors.

Gamma-glutamyl transferase secreted by Helicobacter pylori promotes the development of gastric cancer by affecting the energy metabolism and histone methylation status of gastric epithelial cells.

BACKGROUND: Helicobacter pylori (H. pylori) infection is critical in the development and occurrence of gastric cancer. H. pylori secretes gamma-glutamyl transferase (GGT), which affects energy metabolism and histone methylation in mesenchymal stem cells. However, its effect on human gastric epithelial cells remains unclear. This study aimed to investigate the effects of GGT on energy metabolism and histone methylation in gastric epithelial cells and determine its role in the development and progression of H. pylori-induced gastric cancer. METHODS: A GGT knockout H. pylori strain and mouse gastric cancer model were constructed, and alpha-ketoglutarate (α-KG) was added. The underlying mechanism was investigated using proteomics, immunohistochemistry, Western blotting, and other experimental assays. RESULTS: H. pylori can colonize the host's stomach and destroy the gastric epithelium. GGT secreted by H. pylori decreased the concentration of glutamine in the stomach and increased H3K9me3 and H3K27me3 expression, which promoted the proliferation and migration of gastric epithelial cells. Additionally, α-KG reversed this effect. GGT increased the tumorigenic ability of nude mice. GGT, secreted by H. pylori, promoted the expression of ribosomal protein L15 (RPL15), while GGT knockout and supplementation with α-KG and trimethylation inhibitors reduced RPL15 expression and Wnt signaling pathway expression. CONCLUSIONS: H. pylori secreted GGT decreased the expression of glutamine and α-KG in gastric epithelial cells, increased the expression of histones H3K9me3 and H3K27me3, and activated the Wnt signaling pathway through RPL15 expression, ultimately changing the biological characteristics of the gastric epithelium and promoting the occurrence of gastric cancer. Altered energy metabolism and histone hypermethylation are important factors involved in this process.

Importance of gamma-glutamyl transferase elevation in patients with Fontan-associated liver disease.

AIM: In patients with Fontan-associated liver disease (FALD), gamma-glutamyl transferase (GGT) levels are often elevated, however, its clinical importance is unclear. We investigated the relationship between the clinical course of FALD and GGT levels. METHODS: We enrolled 145 patients with FALD who underwent right-heart catheterization (RHC) and visited our department. Ursodeoxycholic acid (UDCA) was administered to 62 of the patients. Patients with GGT levels <50 and ≥50 U/L were compared. Follow-up RHC was undertaken in 76 patients. Cases in which GGT levels decreased by ≥10% or <50 U/L were defined as improved (n = 33). RESULTS: Patients with GGT levels ≥50 U/L had significantly lower levels of albumin and higher levels of alanine transaminase (ALT) but no significant differences in RHC factors. Over a 4.6-year period, 43.4% showed improvement in GGT levels. Improved cases had significantly lower total bilirubin (1.1 vs. 1.6 mg/dL), AST (22 vs. 28 U/L), and ALT (18 vs. 27 U/L) levels than nonimproved cases (n = 29, p < 0.05), and the change in platelet count (-0.5 vs. -3.0 × 10-4/µL) was significantly lower in the latter (p = 0.03). The improvement rate was significantly higher in UDCA-treated cases (55.2%) with GGT levels ≥50 U/L compared to cases not treated with UDCA (18.2%, p = 0.04). CONCLUSION: In cases of FALD with no improvement in GGT level, the platelet count decreased over time, suggesting progression of fibrosis. Physicians should be aware of the importance of a high GGT level in patients with FALD.

γ-Gammaglutamyl transferase predicts all-cause mortality within three-year intervals in patients undergoing peritoneal dialysis.

OBJECTIVES: Peritoneal dialysis (PD) serves as a vital renal replacement therapy for patients with end-stage kidney disease (ESKD). γ-Gamma-glutamyl transferase (γ-GGT) is a recognized predictor of oxidative stress and mortality. This study aimed to assess the prognostic significance of γ-GGT in predicting all-cause and cardiovascular mortality among PD patients. METHODS: A retrospective study was conducted, enrolling 640 PD patients from a single center. The one-year, three-year, and five-year mortality rates for all causes and cardiovascular causes were evaluated. Kaplan-Meier survival analysis and multivariate Cox regression analysis were performed. RESULTS: Within five years of initiating PD, the observed all-cause mortality rates at one, three, and five years were 11.72%, 16.09%, and 23.44%, while cardiovascular mortality rates were 2.97%, 7.34%, and 11.09%, respectively. Lower γ-GGT levels were associated with decreased all-cause mortality during one-, three-, and five-year follow-ups, along with reduced cardiovascular mortality in the first and third years, as indicated by Kaplan-Meier analysis on median γ-GGT groupings. Multivariate Cox regression analysis showed significantly decreased hazard ratios (HRs) for one- to five-year all-cause mortality and cardiovascular mortality in the lower γ-GGT group compared to higher groups. However, when sex differences were eliminated using separate tertile groupings for males and females, only the one- and three-year all-cause mortality rates demonstrated significantly reduced hazard ratios (HRs) in the lower γ-GGT groups. CONCLUSION: This retrospective study suggests that γ-GGT levels have prognostic significance in predicting one- and three-year all-cause mortality among PD patients when accounting for sex differences.

The discovery of GGT1 as a novel gene for ischemic stroke conferring protection against disease risk in non-smokers and non-abusers of alcohol.

OBJECTIVES: Increased plasma gamma-glutamyl transferase (GGT1) has been identified as a robust and independent risk factor for ischemic stroke (IS), but the molecular mechanisms of the enzyme-disease association are unclear. The present study investigated whether polymorphisms in the GGT1 gene contribute to IS susceptibility. MATERIALS AND METHODS: DNA samples obtained from 1288 unrelated individuals (600 IS patients and 688 controls) were genotyped for common single nucleotide polymorphisms of GGT1 using the MassArray-4 platform. RESULTS: The rs5751909 polymorphism was significantly associated with decreased risk of ischemic stroke regardless sex and age (Pperm ≤ 0.01, dominant genetic model). The haplotype rs4820599A-rs5760489A-rs5751909A showed strong protection against ischemic stroke (OR 0.53, 95 %CI 0.36 - 0.77, Pperm ≤ 0.0001). The protective effect of SNP rs5751909 in the stroke phenotype was successfully replicated in the UK Biobank, SiGN, and ISGC cohorts (P ≤ 0.01). GGT1 polymorphisms showed joint (epistatic) effects on the risk of ischemic stroke, with some known IS-associated GWAS loci (e.g., rs4322086 and rs12646447) investigated in our population. In addition, SNP rs5751909 was found to be strongly associated with a decreased risk of ischemic stroke in non-smokers (OR 0.54 95 %CI 0.39-0.75, Pperm = 0.0002) and non-alcohol abusers (OR 0.43 95 %CI 0.30-0.61, Pperm = 2.0 × 10-6), whereas no protective effects of this SNP against disease risk were observed in smokers and alcohol abusers (Pperm < 0.05). CONCLUSIONS: We propose mechanisms underlying the observed associations between GGT1 polymorphisms and ischemic stroke risk. This pilot study is the first to demonstrate that GGT1 is a novel susceptibility gene for ischemic stroke and provides additional evidence of the genetic contribution to impaired redox homeostasis underlying disease pathogenesis.

Ketamine uropathy: Clinical experience in a high prevalence center.

OBJECTIVES: Ketamine uropathy causes inflammatory changes to the urothelium, manifesting as significant lower urinary tract symptoms, small bladder capacity, and pelvic pain. Upper tract involvement and hydronephrosis can occur. Data from UK centers are limited, and no formal treatment guidelines exist. PATIENTS AND METHODS: All patients with ketamine uropathy presenting to our unit over an 11-year period were identified through operative and clinic lists, emergency presentations, and a prospectively collected local database. Demographic data, biochemical findings, imaging techniques, and both medical and surgical management were recorded. RESULTS: A total of 81 patients with ketamine uropathy were identified from 2011 to 2022; however, a large proportion presented from 2018 onwards. The average age at presentation was 26 years (interquartile range [IQR]: 27-34), 72.8% were male, and average follow-up time was 34 months (IQR: 8-46). Therapeutic interventions included anticholinergic medication, cystodistension, and intravesical sodium hyaluronate. Hydronephrosis was present in 20 (24.7%) patients and nephrostomy insertion was required in six. One patient underwent bladder augmentation surgery. Serum gamma-glutamyl transferase and length of follow-up were significantly higher in patients with hydronephrosis. Adherence to follow-up was poor. CONCLUSIONS: We present a large cohort of patients with ketamine uropathy from a small town in the UK which is unusual. The incidence appears to be rising, in-keeping with increasing recreational ketamine use and should be of concern to urologists. Abstinence is a key aspect of management, and a multi-disciplinary approach works best particularly as many patients are lost to follow-up. The development of formal guidance would be helpful.

Prognostic value of alkaline phosphatase and gamma-glutamyl transferase in patients with metastatic pancreatic cancer.

Background: Pancreatic cancer (PC) is one of the most lethal malignancies worldwide. This study evaluated the prognostic role of serum alanine phosphatase (ALP) and gamma-glutamyl-transferase (GGT) in metastatic PC patients. Materials & methods: 153 patients with metastatic PC receiving first-line treatment with nab-paclitaxel/gemcitabine were retrospectively enrolled in a multicenter study and stratified according to ALP (≤ or >260 U/l) and GGT (≤ or >45.5 U/l) levels. Results: Improved overall survival was recorded in patients with GGT levels ≤45.5 U/l (p < 0.05). In patients with liver metastasis, overall survival was significantly lower in patients with high ALP (p = 0.01) and GGT (p = 0.02). Conclusion: High levels of ALP and GGT were related to a poor prognosis in PC patients with liver metastasis receiving nab-paclitaxel/gemcitabine.

Pancreatic cancer is a deadly form of cancer. This study looked at whether levels of two enzymes, alanine phosphatase (ALP) and gamma-glutamyl-transferase (GGT), in the blood of patients with metastatic pancreatic cancer could predict how long they would live. The study included 153 patients who were receiving their first treatment for metastatic pancreatic cancer. The patients were divided into groups based on whether their ALP and GGT levels were high or low. The researchers found that patients with low GGT levels tended to live longer. Patients with liver metastasis (spread of cancer to the liver) who had high levels of ALP and GGT tended to have a worse prognosis than patients with low levels of these enzymes. Therefore, higher levels of ALP and GGT in the blood may be associated with a poor prognosis in pancreatic cancer patients with liver metastasis who are receiving nab-paclitaxel/gemcitabine treatment.

Cardiohepatic syndrome and its prognostic predictive ability in patients with pulmonary arterial hypertension.

With the development of progressive right ventricular dysfunction, pulmonary arterial hypertension (PAH) is one of the causes of type 2 cardiohepatic syndrome (CHS). Risk assessment, timely and effective management are crucial to improve survival in PAH. Thus, we aimed to evaluate the presence of CHS at diagnosis and its association with prognosis in patients with PAH. One hundred and eighteen consecutive incident patients with PAH between January 2013 and June 2021 were retrospectively included. The presence of CHS was assessed from blood tests taken during diagnostic evaluation and was defined as elevation of at least two of three cholestatic liver parameters; total bilirubin, alkaline phosphatase and gamma-glutamyl transferase. The primary endpoint was all-cause mortality. Patients were followed for a median period of 58 (32-96) months. 23.7% of the patients had CHS at diagnosis. Significantly more patients in CHS (+) group were in intermediate and high-risk categories according to 2015 ESC/ERS guideline, REVEAL 2.0 and REVEAL Lite 2 risk assessment methods (p = .02, .03 and <.001, respectively). The presence of CHS was identified as an independent predictor of mortality (HR: 2.17, 95% CI: 1.03-4.65, p = .03) along with older age (HR: 2.89, 95% CI: 1.50-5.56, p = .001) and higher WHO functional class (HR: 2.57, 95% CI: 1.07-6.22, p = .03). To conclude, presence of CHS at diagnosis in patients with PAH was associated with severe disease and poor prognosis independent of other well known risk factors. As a simple and easy parameter to assess from routinely taken blood tests, CHS should be evaluated in patients with PAH.

Evaluation of potential biomarkers to determine adequate colostrum provision in male dairy-beef calves upon arrival at the rearing facility beyond 14 days of age.

Colostrum consumption is crucial for passive immunization and development of the newborn calf. However, the incidence on failed transfer of passive immunity in male calves destined to dairy-beef production remains high to date. In addition, the lack of an automated procedure to validate the immunization status upon arrival at rearing facilities in calves beyond 14 d of age impedes the identification of failed transfer of passive immunity, and therefore, of those calves at high risk of suffering diseases. For this study, 82 newborn male Holstein calves (43.3 ± 0.86 kg of body weight; mean ± standard error) from a commercial dairy farm were used to investigate potential serum biomarkers of colostrum provision. The potential biomarkers selected were IgG, IgG1, cholesterol, alkaline phosphatase, gamma-glutamyl transferase (GGT), and total protein (TP). Treatments were as follows: high-colostrum (HC; n = 49), in which calves received 4 L of colostrum within the first 2 h after birth and 2 L of colostrum in the next 3 feedings within the first 24 h after birth, for a total of 10 L of colostrum; and low-colostrum (LC; n = 33), in which calves received only 2 L of colostrum within the first 2 h after birth. After colostrum consumption, calves were allocated to individual hutches and fed 2 L of milk replacer twice daily at a concentration of 125 g/L as fed. Starter feed and water were offered ad libitum. At approximately 14 d of age (14.2 ± 0.81 d of age; mean ± standard error) calves were transported 2.5 h to a research unit at IRTA (Torre Marimon, Spain) simulating the arrival to a rearing facility. Blood samples were collected before feeding at birth, 48 h after birth, and at arrival to the rearing facility. Results on the serum concentrations of the potential biomarkers at arrival to the rearing facility showed that IgG, IgG1, GGT, and TP were greater for the HC calves compared with the LC calves. Serum concentrations of cholesterol and alkaline phosphatase did not show differences between treatment groups. Additionally, body weight losses from birth until arrival to the rearing facility were greater for the LC treatment compared with the HC. Because of their low cost, quickness, and ease of measurement, GGT and TP were good indicators of colostrum intake in calves arriving at rearing facilities beyond 14 d of age.

The association between urinary polycyclic aromatic hydrocarbon metabolites and liver function among US population: a cross-sectional study.

Most studies have focused on the pulmonary toxicity of inhaled PAHs to date; therefore, their hepatotoxic consequences are yet unknown. The main aim of this study is to examine the association between urinary polycyclic aromatic hydrocarbons (PAHs) and liver function parameters among the US population. The data included in this study were from the National Health and Nutritional Examination Survey (NHANES) 2003-2016. Finally, we included 2515 participants from seven cycles of the NHANES. Logistic regression was performed to calculate the association between each PAH and liver function parameters (elevated vs. normal) with odds ratio (OR) and 95% confidence intervals (CIs), along with adjustment for confounding variables. P < 0.05 was considered to indicate a statistically significant difference. All analyses were performed using R software 4.0.1. In the present study, all 2515 individuals were aged ≥ 18 years, 1211 males, and 1304 females. The average age normal was 45.56 ± 20.20, and the elevated was 46.04 ± 19.73 years, respectively. The results of logistic regression indicated that increased 9-hydroxyfluorene (OR = 2.11, 95% CI = [1.52, 2.95], P < 0.001), 2-hydroxyfluorene (OR = 1.61, 95% CI = [1.23, 2.11], P < 0.001), and 3-hydroxyfluorene (OR = 1.54, 95% CI = [1.21, 1.95], P < 0.001) were associated with elevated GGT. In conclusion, 9-hydroxyfluorene is associated with elevated GGT level, and the effect of 9-hydroxyfluorene on GGT is modified by other PAHs, which means that 9-hydroxyfluorene has a greater influence on GGT when other PAHs are increased.

Gamma-glutamyl-transferase is associated with incident hip fractures in women and men ≥ 50 years: a large population-based cohort study.

The association of serum gamma-glutamyl-transferase (GGT) with hip fracture risk has not been examined in women and men ≥ 50 years. We show that elevated GGT was associated with increased hip fracture risk, particularly in men. GGT could be a candidate serum marker of long-term hip fracture risk in the elderly. INTRODUCTION: We herein examined a possible relation between serum levels of GGT and hip fracture risk in women and men aged ≥ 50 years, which has not been investigated before. METHODS: In this population-based prospective cohort study, approximately 41,000 women and nearly 33,000 men ≥ 50 years participating in a medical prevention program 1985-2005 in western Austria were followed up for the occurrence of osteoporotic hip fractures during 2003-2013. ICD-10 based discharge diagnoses for hip fracture included S72.0, S72.1, and S72.2 available from all regional hospitals. GGT-related hip fracture risk was ascertained at each participant´s first and last examination during the prevention program. In a subset of 5445 participants, alcohol consumption could be included as a covariate. RESULTS: In men, hip fracture risk rose significantly by 75% and 86% for every tenfold increase of GGT measured at the first and last examination, respectively, and in women, hip fracture risk rose by 22% from the last examination. Elevated GGT (≥ 36 U/l in women, ≥ 56 U/l in men) at the first examination was associated with increased hip fracture risk only in men (HR 1.51, 95% CI 1.25-1.82), and at the last examination in both women (HR 1.14, 95% CI 1.02-1.28) and men (HR 1.61, 95% CI 1.33-1.95). Alcohol consumption had no significant influence on GGT-mediated hip fracture risk in women and men. CONCLUSIONS: Our findings identified an association of elevated GGT and hip fracture in women and men ≥ 50 years and suggest GGT as a candidate serum marker of long-term hip fracture risk in an elderly population.

Gamma-Glutamyl Transferase (γ-GT) - an old dog with new tricks?

Gamma-Glutamyl Transferase (γGT) is a key transferase involved in the transpeptidation of functional gamma-glutamyl groups to various receptor moieties. It performs important roles in antioxidant defence mechanisms, particularly glutathione recycling, xenobiotic metabolism, but analogously may also have a pro-oxidant role. γGT is very sensitive for the diagnosis of liver injury, although it has poor specificity for particular aetiologies. It has been used to reflect temporal changes as a form of monitoring depending on aetiology. Given its cellular role in antioxidant function, it has been investigated as a surrogate biomarker of oxidative stress. It has also been found to be a predictor of mortality across a spectra of non-hepatic disease pathologies, from metabolic and cardiovascular risk to chronic kidney disease and neoplasia. Similarly, it also remains of interest to the insurance industry given an apparent ability to predict mortality, in addition to a historical interest from law enforcement as a marker of chronic alcohol ingestion. Here, we review some of the unique characteristics of this important enzyme, previously considered as a mere specific marker of liver dysfunction, but now with clear extra-hepatic implications and novel applications and utility.

Gamma-glutamyl transferase levels are associated with the occurrence of post-stroke cognitive impairment: a multicenter cohort study.

BACKGROUND: Gamma-glutamyl transferase (GGT) is involved in maintenance of physiological concentrations of glutathione in cells, and protects them from oxidative stress-induced damage. However, its role in post-stroke cognitive impairment (PSCI) remains unknown. Here, we investigated the effects of serum GGT on PSCI. METHODS: We conducted a prospective, multicenter cohort study. A total of 1, 957 participants with a minor ischemic stroke or transient ischemic attack whose baseline GGT levels were measured were enrolled from the Impairment of Cognition and Sleep (ICONS) study of the China National Stroke Registry-3 (CNSR-3). They were categorized into four groups according to quartiles of baseline GGT levels. Cognitive functions were assessed using the Montreal Cognitive Assessment (MoCA) approach. Multiple logistic regression models were performed to evaluate the relationship between GGT and PSCI at 3 months follow-up. RESULTS: Among the 1957 participants, 671 (34.29%) patients suffered PSCI at 3 months follow-up. The highest GGT level quartile group exhibited a lower risk of PSCI in the fully adjusted model [OR (95% CI): 0.69 (0.50-0.96)], relative to the lowest group. Moreover, incorporation of GGT to the conventional model resulted in slight improvements in PSCI outcomes after 3 months (NRI: 12.00%; IDI: 0.30%). CONCLUSIONS: Serum GGT levels are inversely associated with the risk of PSCI, with extremely low levels being viable risk factors for PSCI.

Design and evaluation of novel analogs of 2-amino-4-boronobutanoic acid (ABBA) as inhibitors of human gamma-glutamyl transpeptidase.

Inhibitors of gamma-glutamyl transpeptidase (GGT1, aka gamma-glutamyl transferase) are needed for the treatment of cancer, cardiovascular illness and other diseases. Compounds that inhibit GGT1 have been evaluated in the clinic, but no inhibitor has successfully demonstrated specific and systemic GGT1 inhibition. All have severe side effects. L-2-amino-4­boronobutanoic acid (l-ABBA), a glutamate analog, is the most potent GGT1 inhibitor in vitro. In this study, we have solved the crystal structure of human GGT1 (hGGT1) with ABBA bound in the active site. The structure was interrogated to identify interactions between the enzyme and the inhibitor. Based on these data, a series of novel ABBA analogs were designed and synthesized. Their inhibitory activity against the hydrolysis and transpeptidation activities of hGGT1 were determined. The lead compounds were crystalized with hGGT1 and the structures solved. The kinetic data and structures of the complexes provide new insights into the critical role of protein structure dynamics in developing compounds for inhibition of hGGT1.

Derivation of sex and age-specific reference intervals for clinical chemistry analytes in healthy Ghanaian adults.

OBJECTVIES: This study is aimed at establishing reference intervals (RIs) of 40 chemistry and immunochemistry analytes for Ghanaian adults based on internationally harmonized protocol by IFCC Committee on Reference Intervals and Decision Limits (C-RIDL). METHODS: A total of 501 healthy volunteers aged ≥18 years were recruited from the northern and southern regions of Ghana. Blood samples were analyzed with Beckman-Coulter AU480 and Centaur-XP/Siemen auto-analyzers. Sources of variations of reference values (RVs) were evaluated by multiple regression analysis (MRA). The need for partitioning RVs by sex and age was guided by the SD ratio (SDR). The RI for each analyte was derived using parametric method with application of the latent abnormal values exclusion (LAVE) method. RESULTS: Using SDR≥0.4 as threshold, RVs were partitioned by sex for most enzymes, creatinine, uric acid (UA), bilirubin, immunoglobulin-M. MRA revealed age and body mass index (BMI) as major source of variations of many analytes. LAVE lowered the upper limits of RIs for alanine/aspartate aminotransferase, γ-glutamyl transaminase and lipids. Exclusion of individuals with BMI≥30 further lowered the RIs for lipids and CRP. After standardization based on value-assigned serum panel provided by C-RIDL, Ghanaian RIs were found higher for creatine kinase, amylase, and lower for albumin and urea compared to other collaborating countries. CONCLUSIONS: The LAVE effect on many clinical chemistry RIs supports the need for the secondary exclusion for reliable derivation of RIs. The differences in Ghanaian RIs compared to other countries underscore the importance of country specific-RIs for improved clinical decision making.

Combined Associations of Liver Enzymes and Obesity With Diabetes Mellitus Prevalence: The Tohoku Medical Megabank Community-based Cohort Study.

BACKGROUND: Alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT) are enzymes associated with diabetes mellitus (DM) prevalence. However, limited information is available regarding the association of liver enzymes and DM consistently present in obese and non-obese individuals. We examined whether the combination of ALT and GGT enzymes is associated with the prevalence of DM, regardless of obesity, in a general Japanese population. METHODS: We conducted a cross-sectional study of 62,786 participants aged ≥20 years who lived in Miyagi and Iwate, Japan. We divided all the participants into eight groups according to the ALT level (low: <30 IU/L and high: ≥30 IU/L), GGT level (low: <50 IU/L and high: ≥50 IU/L), and the presence of obesity. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression analysis, adjusting for potential confounders, to determine associations of the combination of ALT and GGT levels and obesity with DM prevalence. RESULTS: Overall, 6,008 participants (9.6%) had DM. Compared to non-obese individuals with low ALT and GGT levels, the participants with high ALT and GGT levels had high ORs for DM in both obese (OR 4.06; 95% CI, 3.61-4.56) and non-obese groups (OR 2.19; 95% CI, 1.89-2.52). The obese group had high ORs for DM, even at low ALT and GGT levels. CONCLUSION: High ALT and GGT levels are associated with DM prevalence in obese and non-obese participants. This finding suggests that correcting ALT and GGT levels and controlling obesity are important for the prevention of DM.

Plasma-induced nanoparticle aggregation for stratifying COVID-19 patients according to disease severity.

Stratifying patients according to disease severity has been a major hurdle during the COVID-19 pandemic. This usually requires evaluating the levels of several biomarkers, which may be cumbersome when rapid decisions are required. In this manuscript we show that a single nanoparticle aggregation test can be used to distinguish patients that require intensive care from those that have already been discharged from the intensive care unit (ICU). It consists of diluting a platelet-free plasma sample and then adding gold nanoparticles. The nanoparticles aggregate to a larger extent when the samples are obtained from a patient in the ICU. This changes the color of the colloidal suspension, which can be evaluated by measuring the pixel intensity of a photograph. Although the exact factor or combination of factors behind the different aggregation behavior is unknown, control experiments demonstrate that the presence of proteins in the samples is crucial for the test to work. Principal component analysis demonstrates that the test result is highly correlated to biomarkers of prognosis and inflammation that are commonly used to evaluate the severity of COVID-19 patients. The results shown here pave the way to develop nanoparticle aggregation assays that classify COVID-19 patients according to disease severity, which could be useful to de-escalate care safely and make a better use of hospital resources.

Diagnostic values of plasma matrix metalloproteinase-7, interleukin-8, and gamma-glutamyl transferase in biliary atresia.

Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and liver fibrosis. The early diagnosis of BA is still challenging. This study aimed to evaluate the diagnostic values of matrix metalloprotease-7 (MMP-7), interleukin-8 (IL-8), and gamma-glutamyl transferase (GGT) in BA. Infants diagnosed with BA and non-BA between 2013 and 2018 were retrospectively analyzed. Plasma levels of MMP-7, IL-8, and GGT were measured in these infants. The receiver operating characteristic (ROC) curves and area under the ROC curve (AUC) were used to assess the diagnostic values of MMP-7, IL-8, and GGT. The expression of MMP-7 and IL-8 in the livers was detected by immunofluorescence staining. A total of 229 infants were enrolled in this study: 156 BA infants and 73 non-BA infants including 16 ones with infantile hepatitis syndrome. The plasma levels of MMP-7, IL-8, and GGT in BA infants had a median of 11.8 ng/mL (interquartile range, IQR: 5.3-57.5), 1.5 ng/mL (IQR: 1.0-2.8), and 381.0 U/L (IQR: 197.0-749.0), respectively, which were higher than non-BA subjects [MMP-7, 4.4 ng/mL (IQR: 3.3-6.1); IL-8, 0.7 ng/mL (IQR: 0.5-1.0); GGT, 59.0 U/L (IQR: 26.0-124.0)]. The AUC values of MMP-7, IL-8, and GGT for the diagnosis of BA were 0.8035, 0.8083, and 0.9126, respectively. The AUC values of MMP-7 + IL-8, MMP-7 + GGT, IL-8 + GGT, and MMP-7 + IL-8 + GGT for the diagnosis of BA were 0.8248, 0.9382, 0.9168, and 0.9392, respectively. The AUC values of MMP-7, IL-8, and GGT for differentiating BA infants with cholic stool from non-BA infants with cholic stool were 0.8006, 0.8258, and 0.9141, respectively. The expression of MMP-7 and IL-8 was increased in the cholangiocytes in BA livers.   Conclusion: Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA and may be reliable biomarkers for BA. What is Known: • Biliary atresia (BA) is a severe cholestatic liver disease in children featuring cholestasis and progressive liver fibrosis. • Although early diagnosis of BA is crucial for good outcomes, it remains a clinical challenge. What is New: • Plasma MMP-7, IL-8, and GGT alone or a combination of them has good accuracy to differentiate BA from non-BA. • Plasma MMP-7, IL-8, and GGT have good accuracy for differentiating BA infants with cholic stool from non-BA infants with cholic stool.

The utility of shear wave elastography and serum biomarkers for diagnosing biliary atresia and predicting clinical outcomes.

To investigate the utility of liver stiffness measurement by shear wave elastography (SWE) and several commonly used biomarkers in differentiating biliary atresia (BA) from other causes of cholestasis (non-BA) patients within 45 days and in predicting the postoperative prognosis. A consecutive series of medical records of patients presenting with cholestasis within 45 days in our institution between February 2016 and December 2020 was collected. The BA diagnosis was confirmed by intraoperative cholangiography (IOC). Other causes of cholestasis were confirmed by IOC, liver biopsy, genetic analysis, or recovery after conservative treatment. Preoperative and postoperative data were analyzed. A total of 156 patients were included, consisting of BA (n = 83) and non-BA (n = 73) cases. SWE and serum gamma-glutamyl transferase (GGT) showed better discriminative utility. The optimal cutoff values for SWE and GGT were > 7.10 kPa and > 195.4 U/L, with AUC of 0.82 (95% CI, 0.76-0.89; p < 0.0001) and 0.87 (95% CI, 0.82-0.93; p < 0.0001), respectively. Subgroup analysis showed the increased discriminative performance of SWE with age. Multivariable logistic regression analysis showed better diagnostic performance for SWE (adjusted OR, 35.03; 95% CI, 7.12-172.50) and GGT (adjusted OR, 24.70; 95% CI, 6.55-93.18) after adjusting for other confounders. The 30-day postoperative to preoperative serum direct bilirubin (DB) level, DB (post-30:pre), of > 0.3 showed the best predictive value for the need of liver transplantation, with HR of 6.15 (95% CI 1.95-19.38, P = 0.042).Conclusion: Serum GGT level and liver stiffness measurement by SWE showed the best discriminative utility. The diagnostic performance of SWE increased with age. A DB (post-30:pre) value > 0.3 was associated with the need for liver transplantation in later life. What is Known: • Liver stiffness measurement by shear wave elastography (SWE) could help discriminate biliary atresia (BA) from other causes of cholestasis, with sensitivity of 70-90%. • The postoperative total bilirubin less than 2 mg/dL within the first 3 months was a predictor of transplant-free survival. What is New: • The diagnostic performance of liver stiffness measurement by SWE increased with age. • The 30-day postoperative direct bilirubin (DB) level to preoperative DB level, DB (post-30:pre), is a predictor for short-term clinical outcomes.

In-hospital mortality in SARS-CoV-2 stratified by gamma-glutamyl transferase levels.

BACKGROUND: This study investigates in-hospital mortality amongst patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its relation to serum levels of gamma-glutamyl transferase (GGT). METHODS: Patients were stratified according to serum levels of gamma-glutamyl transferase (GGT) (GGT<50 IU/L or GGT≥50 IU/L). RESULTS: A total of 802 participants were considered, amongst whom 486 had GGT<50 IU/L and a mean age of 48.1 (16.5) years, whilst 316 had GGT≥50 IU/L and a mean age of 53.8 (14.7) years. The chief sources of SARS-CoV-2 transmission were contact (366, 45.7%) and community (320, 40%). Most patients with GGT≥50 IU/L had either pneumonia (247, 78.2%) or acute respiratory distress syndrome (ARDS) (85, 26.9%), whilst those with GGT<50 IU/L had hypertension (141, 29%) or diabetes mellitus (DM) (147, 30.2%). Mortality was higher amongst patients with GGT≥50 IU/L (54, 17.1%) than amongst those with GGT<50 IU/L (29, 5.9%). More patients with GGT≥50 required high (83, 27.6%) or low (104, 34.6%) levels of oxygen, whereas most of those with GGT<50 had no requirement of oxygen (306, 71.2%). Multivariable logistic regression analysis indicated that GGT≥50 IU/L (odds ratio [OR]: 2.02, 95% confidence interval [CI]: 1.20-3.45, p=0.009), age (OR: 1.05, 95% CI: 1.03-1.07, p<0.001), hypertension (OR: 2.06, 95% CI: 1.19-3.63, p=0.011), methylprednisolone (OR: 2.96, 95% CI: 1.74-5.01, p<0.001) and fever (OR: 2.03, 95% CI: 1.15-3.68, p=0.016) were significant predictors of all-cause cumulative mortality. A Cox proportional hazards regression model (B = -0.68, SE =0.24, HR =0.51, p = 0.004) showed that patients with GGT<50 IU/L had a 0.51-times lower risk of all-cause cumulative mortality than patients with GGT≥50 IU/L. CONCLUSION: Higher levels of serum GGT were found to be an independent predictor of in-hospital mortality.