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Objective: To investigate the effect of capecitabine on the sensitivity of oxaliplatin and on the level of transcription factor forkhead box P1 (FOXP1) and gamma-glutamyl transpeptidase (GGT) in patients with intermediate and advanced gastric cancer. Methods: A total of 152 patients with intermediate and advanced gastric cancer diagnosed and treated in our hospital from April 2018 to May 2019 was selected as the research objects, and their clinical data were retrospectively analyzed. According to the different treatment methods, they were divided into the study group and the control group, with 76 cases in each group. The patients in the control group received with oxaliplatin, while the patients in the study group received with capecitabine on the basis of the control group. The therapeutic effect was evaluated according to the therapeutic effect evaluation criteria of solid tumors. The FOXP1 expression level in gastric cancer tissues was detected using immunohistochemistry. Serum levels of GGT were measured by chemiluminescence. The prognostic factors were analyzed by COX regression model, and the Kaplan-Meier survival curve was used to analyze the relationship between the influencing factors and the survival of gastric cancer. Results: The effective rate of capecitabine combined with oxaliplatin and oxaliplatin alone in the treatment of patients with intermediate and advanced gastric cancer were 94.74 % and 76.32 % respectively. Capecitabine enhanced the sensitivity of intermediate and advanced gastric cancer to oxaliplatin (P 0.05). After treatment, the low expression rate of FOXP1 and serum GGT level were both significantly decreased, and those in the study group were lower than those in the control group (P 0.05). The 1-year survival rates of the study group and the control group were 90.79 % and 78.95 %, while the 3-year survival rates of the study group and the control group were 75.00 % and 51.32 %, respectively. Both the 1-year and 3-year survival rate of the study group was higher than that in the control group (P

Background & Aims: Porto-sinusoidal vascular disorder (PSVD) is a group of vascular disorders characterized by lesions involving portal venules and sinusoids, irrespective of the presence of portal hypertension. Liver biopsy is essential for diagnosis. In a single-center study, we demonstrated high rates of PSVD in patients with persistently elevated gamma-glutamyltransferase (GGT). This multicenter study aims to establish PSVD prevalence in a larger dataset of individuals with persistent and unexplained GGT elevation, and to identify associated risk factors. Methods: The study included all patients who underwent liver biopsy for persistent and unexplained GGT elevation in five Italian hepatology units between March 2015 and December 2021. Results: A total of 144 patients met the inclusion criteria. The majority were males (76/144, 52.8%) and mean age was 51.9 years (range 19-74). Only 12 (8.3%) had liver stiffness measurements (LSM) >10 kPa, while 7 (4.8%) had ultrasound evidence of portal hypertension. Histological findings were consistent with PSVD in 96 patients (67%). Alternative diagnoses were steatohepatitis in 13 (9%), sarcoidosis in 3 (2%) and congenital hepatic fibrosis in 3 (2%) patients. Histological findings were non-specific in 29 (20%) patients. PSVD was associated with male sex (odds ratio [OR] 2.60, 95% CI 1.13-5.99), LSM

Background & Aims: We conducted an individual patient data meta-analysis to establish stiffness cut-off values for magnetic resonance elastography (MRE) in staging liver fibrosis and to assess potential confounding factors., Methods: A systematic review of the literature identified studies reporting MRE data in patients with NAFLD. Data were obtained from the corresponding authors. The pooled diagnostic cut-off value for the various fibrosis stages was determined in a two-stage meta-analysis. Multilevel modelling methods were used to analyse potential confounding factors influencing the diagnostic accuracy of MRE in staging liver fibrosis., Results: Eight independent cohorts comprising 798 patients were included in the meta-analysis. The area under the receiver operating characteristic curve (AUROC) for MRE in detecting significant fibrosis was 0.92 (sensitivity, 79%; specificity, 89%). For advanced fibrosis, the AUROC was 0.92 (sensitivity, 87%; specificity, 88%). For cirrhosis, the AUROC was 0.94 (sensitivity, 88%, specificity, 89%). Cut-offs were defined to explore concordance between MRE and histopathology: ≥F2, 3.14 kPa (pretest probability, 39.4%); ≥F3, 3.53 kPa (pretest probability, 24.1%); and F4, 4.45 kPa (pretest probability, 8.7%). In generalized linear mixed model analysis, histological steatohepatitis with higher inflammatory activity (odds ratio 2.448, 95% CI 1.180-5.079, p <0.05) and high gamma-glutamyl transferase (GGT) concentration (>120U/L) (odds ratio 3.388, 95% CI 1.577-7.278, p <0.01] were significantly associated with elevated liver stiffness, and thus affecting accuracy in staging early fibrosis (F0-F1). Steatosis, as measured by magnetic resonance imaging proton density fat fraction, and body mass index(BMI) were not confounders., Conclusions: MRE has excellent diagnostic performance for significant, advanced fibrosis and cirrhosis in patients with NAFLD. Elevated inflammatory activity and GGT level may lead to overestimation of early liver fibrosis, but anthropometric measures such as BMI or the degree of steatosis do not., Impact and Implications: This individual patient data meta-analysis of eight international cohorts, including 798 patients, demonstrated that MRE achieves excellent diagnostic accuracy for significant, advanced fibrosis and cirrhosis in patients with NAFLD. Cut-off values (significant fibrosis, 3.14 kPa; advanced fibrosis, 3.53 kPa; and cirrhosis, 4.45 kPa) were established. Elevated inflammatory activity and gamma-glutamyltransferase level may affect the diagnostic accuracy of MRE, leading to overestimation of liver fibrosis in early stages. We observed no impact of diabetes, obesity, or any other metabolic disorder on the diagnostic accuracy of MRE., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Gamma glutamyl transferase (GGT) is related to oxidative stress and an indicator for liver damage. We investigated the association between air pollution and GGT in a large Austrian cohort (N = 116,109) to better understand how air pollution affects human health. Data come from voluntary prevention visits that were routinely collected within the Vorarlberg Health Monitoring and Prevention Program (VHM&PP). Recruitment was ongoing from 1985 to 2005. Blood was drawn and GGT measured centralized in two laboratories. Land use regression models were applied to estimate individuals' exposure at their home address for particulate matter (PM) with a diameter of <2.5 μm (PM2.5), <10 μm (PM10), fraction between 10 μm and 2.5 μm (PMcoarse), as well as PM2.5 absorbance (PM2.5abs), NO 2 , NO x and eight components of PM. Linear regression models, adjusting for relevant individual and community-level confounders were calculated. The study population was 56 % female with a mean age of 42 years and mean GGT was 19.0 units. Individual PM2.5 and NO 2 exposures were essentially below European limit values of 25 and 40 μg/m 3 , respectively, with means of 13.58 μg/m 3 for PM2.5 and 19.93 μg/m 3 for NO 2 . Positive associations were observed for PM2.5, PM10, PM2.5abs, NO 2 , NO x , and Cu, K, S in PM2.5 and PM10 fractions and Zn mainly in PM2.5 fraction. The strongest association per interquartile range observed was an increase of serum GGT concentration by 1.40 % (95 %-CI: 0.85 %; 1.95 %) per 45.7 ng/m 3  S in PM2.5. Associations were robust to adjustments for other biomarkers, in two-pollutant models and the subset with a stable residential history. We found that long-term exposure to air pollution (PM2.5, PM10, PM2.5abs, NO 2 , NO x ) as well as certain elements, were positively associated with baseline GGT levels. The elements associated suggest a role of traffic emissions, long range transport and wood burning., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: In the context of fitness certification to hold the driving license, GGT and CDT have been used, sometimes in combination (γ-CDT), to exclude chronic alcohol abuse. The present study was carried out with the aim of comparing the power of these biomarkers as tools for the objective screening of subjects at high risk of alcohol-associated traffic injuries., Methods: 288 male drivers admitted to hospital after traffic accidents were examined by determination of GGT, CDT and BAC. The degree of association of GGT, CDT and γ-CDT with BAC was analysed using non-parametric statistics., Results: Partitioning the cases using the cut-off concentrations of 0.5 g/L for BAC (the legal limit adopted in most European countries), 55 U/L for GGT and 1.9% for CDT, a highly significant difference was found between the frequency of elevated GGT or CDT in cases where BAC was within the legal limits and those with elevated BAC values (Fisher's exact test: p < 0.001). However, the calculation of the odds ratio showed a much higher increase for CDT (28 times) than for GGT (6 times) in those drivers with a BAC above the Italian legal limit in comparison with those showing a BAC within the cut-off; conversely, γ-CDT does not provide any significant advantage vs. CDT alone., Conclusions: Both GGT and CDT provide objective evidence of an association with the occurrence of alcohol-related severe traffic accidents, but CDT shows superior association with these events. Therefore, CDT, notwithstanding higher costs, should be preferred in a forensic/certification context., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: Cisplatin is a potent chemotherapeutic agent whose therapeutic application is hindered by the associated nephrotoxicity. Cisplatin-evoked nephrotoxicity has been largely attributed to the induction of oxidative stress and inflammatory responses. The current study aimed at investigating the ability of ergothioneine to mitigate cisplatin-evoked nephrotoxicity and to elucidate the underlining molecular mechanisms., Main Methods: Wistar rats were treated with a daily dose of ergothioneine (70 mg/kg, po) for fourteen days and a single dose of cisplatin (5 mg/kg, ip) on day ten. On day fifteen, kidneys and blood specimens were collected and subjected to Western blotting, ELISA, histopathological, and spectrophotometric analysis., Key Findings: Ergothioneine significantly enhanced renal function in cisplatin-treated rats as manifested by increased GFR and decreased serum creatinine and blood urea nitrogen. Ergothioneine effectively reduced the cisplatin-induced oxidative stress and mitigated apoptosis and the histopathological changes. Mechanistically, ergothioneine induced the expression of the antioxidant transcription factor Nrf2 and up-regulated its downstream targets NQO1 and HO-1. Equally important, ergothioneine inhibited γ-glutamyl transpeptidase that plays crucial roles in biotransformation of cisplatin into a toxic metabolite. Additionally, it reduced the pro-apoptotic protein p53 and the inflammatory transcription factor NF-κB along with its downstream pro-inflammatory cytokines TNF-α and IL-1β., Significance: The results of the current work shed the light on the ameliorating effect of ergothioneine on cisplatin-evoked nephrotoxicity that is potentially mediated through modulation of Nrf2, p53, and NF-κB signaling and inhibition of γ-glutamyl transpeptidase. This findings support the potential application of ergothioneine in controlling cisplatin-associated nephrotoxicity although clinical investigations are warranted., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Our study aimed to formulate a nomogram based on the albumin-to-fibrinogen ratio (AFR) and gamma-glutamyl transpeptidase-to-platelet ratio (GPR) to predict the prognosis of hepatocellular carcinoma (HCC) patients after curative hepatic resection., Methods: A total of 825 HCC patients who underwent curative resection from 2008 to 2015 in West China Hospital of Sichuan University were divided into a training (n = 616) and a validation (n = 209) cohort. The AFR-GPR risk stratification was generated and confirmed by multivariate analysis. Nomograms for recurrence-free survival (RFS) and overall survival (OS) were constructed. The concordance indexes (C-index), calibration, and decision curve analysis (DCA) were used to assess the predictive performance and clinical benefits of the nomograms., Results: The AFR-GPR risk stratification was the independent prognostic factor for RFS (p = 0.044) and OS (p = 0.002) in the training cohort and integrated into the construction of nomograms. The C-indexes of RFS and OS in the training and validation cohorts were 0.654 (95%CI: 0.626-0.681)/0.699 (95%CI: 0.654-0.743) and 0.699 (95%CI: 0.668-0.729)/0.736 (95%CI: 0.684-0.787), respectively. Furthermore, the C-indexes of the nomograms were greater than those of other conventional staging systems., Conclusion: Our nomograms based on the AFR-GPR risk stratification presented the more reliable, convenient and accurate prognostic predictions for HCC patients., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Acacia catechu (A. catechu) or Khair (Hindi) is used in several herbal preparations in the Ayurvedic system of medicine in India. Traditionally, this drug is beneficial against several gastrointestinal and stomach related ailments, and leprosy. The present investigation was carried out to evaluate the sub-acute oral toxicity of the ethanolic extract of A. catechu seeds in Wistar albino rats. Results obtained from the quantitative chemical analysis of A. catechu seed extract were compared with commercially available standards. A. catechu seed extract was administered orally at the doses of 250, 500 and 1000 mg/kg b.w. daily for 28 days. General behavior, bodyweight and mortality were examined during the entire study period. At the end of 28 days, hematological and biochemical parameters along with the relative organ weights were determined. It was observed that the extract did not induce death or any significant changes in the body weight, relative weight of vital organs and in hematological parameters for up to a dose of 1000 mg/kg. The oral administration of the plant extract did not produce any significant changes in the levels of glucose. In addition, there were no significant changes in the activity of both hepatotoxic and nephrotoxic marker enzymes in the serum. Oral administration of A. catechu also did not produce any significant changes in the levels of oxidative markers. Furthermore, the findings from the biochemical studies were, well corroborated with the histological findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Purpose: Genetic testing in pediatric cholestasis can be very informative but genetic causes have not been fully characterized., Methods: Exome sequencing and positional mapping in seven families with cholestatic liver disease and negative clinical testing for known disease genes., Results: KIF12, which encodes a microtubule motor protein with a tentative role in cell polarity, was found to harbor three homozygous likely deleterious variants in three families with sclerosing cholangitis. KIF12 expression is dependent on HNF-1β, deficiency which is known to cause bile duct dysmorphogenesis associated with loss of KIF12 expression. In another extended family, we mapped an apparently novel syndrome of sclerosing cholangitis, short stature, hypothyroidism, and abnormal tongue pigmentation in two cousins to a homozygous variant in PPM1F (POPX2), a regulator of kinesin-mediated ciliary transport. In the fifth family, a syndrome of normal gamma glutamyltransferase (GGT) cholestasis and hearing loss was found to segregate with a homozygous truncating variant in USP53, which encodes an interactor with TJP2. In the sixth family, we mapped a novel syndrome of transient neonatal cholestasis, intellectual disability, and short stature to a homozygous variant in LSR, an important regulator of liver development. In the last family of three affected siblings, a novel syndrome of intractable itching, hypercholanemia, short stature, and intellectual disability was mapped to a single locus that contains a homozygous truncating variant in WDR83OS (C19orf56), known to interact with ATP13A2 and BSEP., Conclusion: Our results expand the genetic heterogeneity of pediatric cholestatic liver disease and highlight the vulnerability of bile homeostasis to a wide range of molecular perturbations.

Objective: To evaluate associations between total serum γ-glutamyltransferase activity (GGT) and biomarkers of arteriosclerosis in the Multi-Ethnic Study of Atherosclerosis (MESA), including 6783 participants from four ethnic subgroups, i.e., White, Chinese, Black and Hispanic., Methods: Associations between fasting total serum GGT activity and oxidized low-density lipoproteins (oxLDL), interleukin-6 (IL-6), C-reactive protein (CRP), and soluble intercellular adhesion molecule-1 (sICAM-1) were assessed. Following evaluation of linear trends between GGT and biomarkers of interest, multivariable linear regression models were serially adjusted for age, gender, site, ethnicity (M1); M1+lifestyle variables (M2); M2+traditional cardiovascular risk factors plus medications (M3); and M3+metabolic status (M4). Interactions were evaluated between GGT and age and ethnicity in all models., Results: Linear trends were positive and significant between GGT and oxLDL, IL-6, CRP and sICAM-1 in crude models, and trends remained significant in all ethnic subgroups for CRP (p<0.0001) and sICAM-1 (p<0.001), and for IL-6 except in the Chinese. Trends between GGT and oxLDL were significant in the entire cohort and the White subgroup (p<0.0001), but not in other ethnic subgroups. Multivariable models demonstrated continuous strong, positive associations between GGT and CRP, IL-6 and sICAM-1. Associations between GGT and oxLDL were attenuated upon adjustment for LDL-C and other traditional risk factors. All models were attenuated with adjustment for metabolic status. No age interactions were evident., Conclusions: Our findings support the hypothesis that total serum GGT activity represents the impact of metabolic disease on vascular injury and atherosclerosis., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

γ-Glutamyl transferase (GGT) is useful as a marker in pathological conditions, including several types of cancer. We optimized the histochemical detection of GGT to assay the gene expression profiles of phenotype-specific cells selected by laser capture microdissection (LCM). For optimization, we used the livers of rats subjected to hepatocarcinogenesis. This model induced nodules of hepatocytes and tumors with GGT activity. To obtain sufficient high-quality RNA after histochemistry and LCM, we included an RNase inhibitor and air-dried the tissue sections. This optimization allowed the visualization of GGT activity in situ and a yield of 1.4 to 2.0 μg of total RNA from 15 to 18 mm² of microdissected tissue (20 µm thickness). The average RNA integrity number in GGT-positive tissue, determined by chip-capillary electrophoresis, was 6.9, and the 28S/18S ribosomal RNA (rRNA) ratio was 1.4. The RNAs were processed for the Rat Gene 1.0 ST Array (Affymetrix). Comparable quality control metrics, such as signal intensity and RNA degradation plots, were found between the LCM samples and non-LCM tissue. The increased expression of Ggt1 expected in GGT-positive tissue was confirmed by microarrays and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). This optimization provided a suitable method for whole-transcript analysis of GGT-positive tissue isolated using LCM., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background & Aims: In spite of the high incidence of hepatic encephalopathy (HE) in cirrhosis, there are few observational studies., Methods: We performed an analysis to define the characteristics of HE and associated features using the database of the Canonic Study. Clinical, laboratory and survival data of 1348 consecutive cirrhotic patients admitted with an acute decompensation were compared according to the presence (n=406) or absence of HE and of acute-on-chronic liver failure (ACLF) (n=301)., Results: HE development was independently associated with previous HE episodes; survival probabilities worsen in relation to the presence and grade of HE. There were marked differences between HE associated (n=174) and not associated (n=286) to ACLF. HE not associated with ACLF occurred in older cirrhotics, inactive drinkers, without severe liver failure or systemic inflammatory reaction and in relation to diuretic use. In contrast, HE associated with ACLF occurred in younger cirrhotics, more frequently alcoholics, with severe liver failure and systemic inflammatory reaction, and in relation to bacterial infections, active alcoholism and/or dilutional hyponatremia. Prognosis was relatively preserved in the first and extremely poor in the second group. Independent risk factors of mortality in patients with HE were age, bilirubin, INR, creatinine, sodium, and HE grade., Conclusions: In cirrhosis, previous HE identifies a subgroup of patients that is especially vulnerable for developing new episodes of HE. The course of HE appears to be different according to the presence of ACLF., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Protease inhibitors (PI) with peginterferon/ribavirin have significantly improved SVR rates in HCV G1 patients. Their use to treat HCV recurrence after liver transplantation (LT) is a challenge., Methods: This cohort study included 37 liver transplant recipients (male, 92%, age 57 ± 11 years), treated with boceprevir (n=18) or telaprevir (n=19). The indication for therapy was HCV recurrence (fibrosis stage ≥F2 (n=31, 83%) or fibrosing cholestatic hepatitis (n=6, 16%)., Results: Eighteen patients were treatment-naive, five were relapsers and fourteen were non-responders to dual therapy after LT. Twenty-two patients received cyclosporine and fifteen tacrolimus. After 12 weeks of PI therapy, a complete virological response was obtained in 89% of patients treated with boceprevir, and 58% with telaprevir (p=0.06). The end of treatment virological response rate was 72% (13/18) in the boceprevir group and 40% (4/10) in the telaprevir group (p=0.125). A sustained virological response 12 weeks after treatment discontinuation was observed in 20% (1/5) and 71% (5/7) of patients in the telaprevir and boceprevir groups, respectively (p=0.24). Treatment was discontinued in sixteen patients (treatment failures (n=11), adverse events (n=5)). Infections occurred in ten patients (27%), with three fatal outcomes (8%). The most common adverse effect was anemia (n=34, 92%), treated with erythropoietin and/or a ribavirin dose reduction; thirteen patients (35%) received red blood cell transfusions. The cyclosporine dose was reduced by 1.8 ± 1.1-fold and 3.4 ± 1.0-fold with boceprevir and telaprevir, respectively. The tacrolimus dose was reduced by 5.2 ± 1.5-fold with boceprevir and 23.8±18.2-fold with telaprevir., Conclusions: Our results suggest that triple therapy is effective in LT recipients, particularly those experiencing a severe recurrence. The occurrence of anemia and drug-drug interactions, and the risk of infections require close monitoring., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Hirmi Valley liver disease was first reported in 2001 in Tigray, Ethiopia. 591 cases, including 228 deaths, were reported up to December 2009. The pyrrolizidine alkaloid acetyllycopsamine was detected in stored grain and residents reported adding the pesticide DDT (dichlorodiphenyldichloroethylene) directly to their food stores. We aimed to characterise the clinical features of the disease, and explore the role of these chemicals in its aetiology., Methods: 32 cases were examined and full clinical histories taken. Nine cases underwent liver biopsy in hospitals. Serum and urine samples were collected from cases and controls. Urine was analysed for acetyllycopsamine by UPLC-MS. Total DDT in serum was measured by ELISA. Hepatotoxicity of DDT and acetyllycopsamine alone or in combination was explored in C57BL/6J mice., Results: Clinical presentation included epigastric pain, abdominal swelling, bloody diarrhoea, hepatomegaly, splenomegaly, and ascites. Histology revealed acute injury characterised by centrilobular necrosis or chronic injury with bile ductular reaction, cytomegaly and fibrosis but no hepatic vein occlusion. Acetyllycopsamine was detected in urine samples taken in the affected area with significantly greater concentrations in 45 cases than in 43 controls (p=0.02). High levels of DDT (>125 ppb) were detected in 78% of serum samples. In mice, DDT (3 × 75 mg/kg) significantly increased the hepatotoxicity (plasma ALT, p=0.0065) of acetyllycopsamine (750 mg/kg), and in combination induced liver pathology similar to Hirmi Valley liver disease including centrilobular necrosis and cytomegaly., Conclusions: This novel form of disease appears to be caused by co-exposure to acetyllycopsamine and DDT., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Iron overload is known to cause diabetes. However, the underlying mechanism is poorly understood. We therefore studied the association of different markers of iron metabolism, namely ferritin, erythrocyte protoporphyrin and transferrin saturation (TSAT, as defined by a percentage of transferrin that is saturated with iron) with pre-diabetes (preDM) in US adults without chronic kidney disease, anemia, and iron deficiency., Methods: Data on 2575 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2002 who were free of diabetes, chronic kidney disease, iron deficiency, and anemia were analyzed. Data on 3876 participants of the NHANES III (1988-1994) were used as replication. Homeostasis model assessment of insulin resistance (HOMA-IR), blood glycosylated hemoglobin level (HbA1C), fasting glucose, insulin, and preDM (defined as a fasting plasma glucose 100-125 mg/dl or an HBA1C value 5.7-6.4%) were measured as the outcomes., Results: Logistic regression analyses indicated independent associations of high ferritin (Ptrend = 0.028) and low TSAT (P(trend) = 0.029) with preDM after adjusting for sociodemographics, physical activity (active/sedementary), metabolic and inflammatory markers (triglycerides, total cholesterol, HDL cholesterol, mean arterial pressure, CRP, white cell count, and albumin), and liver enzymes (GGT, Alk phos, AST, and ALT). The NHANES III data showed similar associations. Combining the results showed a more significant association for high ferritin (P(meta) = 0.016) and low TSAT (P(meta) = 0.002). Moreover, TSAT was associated with HbA1C, fasting glucose, insulin, and HOMA-IR (P(meta) ≤ 0.001)., Conclusions: Higher ferritin and lower TSAT are associated with higher risk of preDM in a general population without confounding diseases. Further research is needed to examine the underlying mechanism of these two indices, especially TSAT, in the pathophysiology of preDM., (Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background and Aims: Fatty liver index (FLI), a surrogate parameter for nonalcoholic fatty liver disease, is an emerging risk factor for cardiovascular diseases and mortality. We aimed to evaluate whether FLI is associated with all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer in a cohort of subjects routinely referred to coronary angiography., Methods and Results: FLI was calculated using BMI (body mass index), waist circumference (WC), triglycerides (TG) and gamma-glutamyl transferase (GGT) in 3270 subjects who were referred to coronary angiography (1997-2000). The main outcome measures were Cox proportional hazard ratios (HRs) for mortality from all causes, cardiovascular causes, non-cardiovascular causes, and fatal cancer. After a median follow-up time of 7.7 years, 740 subjects (22.6%) had died. There were 437 deaths due to cardiovascular disease and 303 deaths due to non-cardiovascular disease. Age-, sex-, and BMI-adjusted HRs (with 95% confidence intervals) for all-cause, cardiovascular, and non-cardiovascular mortality in the highest compared to the lowest FLI quartile were 2.56 (1.90-3.43; p < 0.001), 2.17 (1.47-3.22; p < 0.001), and 3.49 (2.16-5.66; p < 0.001), respectively. In age-, sex-, and BMI-adjusted analyzes, we found no significant association of FLI with fatal cancer. Multivariate adjusted HRs for all-cause, cardiovascular, non-cardiovascular mortality, and fatal cancer in the highest compared to the lowest FLI quartile were 2.17 (1.58-2.99; p < 0.001), 1.64 (1.07-2.51; p = 0.023), 3.72 (2.22-6.24; p < 0.001), and 2.33 (1.01-5.41; p = 0.048) respectively., Conclusion: In subjects referred to coronary angiography, high FLI levels are independently associated with increased all-cause, cardiovascular, and non-cardiovascular mortality as well as fatal cancer., (© 2013 Elsevier B.V. All rights reserved.)

A soluble form of CD26/dipeptidyl peptidase 4 (sCD26/DPP4) is found in serum and it has DPP4 enzymatic activity. We investigated whether the serum level of sCD26/DPP4 was influenced by the oral glucose tolerance test (OGTT) in healthy subjects. The serum sCD26/DPP4 level increased significantly from 824.5 ng/mL (interquartile range, from 699.0 to 1050 ng/mL) at baseline to a peak of 985.0 ng/mL (interquartile range, from 796.5 to 1215 ng/mL) during the OGTT (P < 0.0001). The peak sCD26/DPP4 level correlated positively with the baseline age and body mass index, and fasting plasma glucose (FPG), homeostasis model assessment of insulin resistance (HOMA-IR), triglycerides (TG), alanine aminotransferase, and γ-glutamyl transpeptidase (GGT) levels whereas it correlated negatively with high-density lipoprotein (HDL) cholesterol and the serum levels of total and high-molecular weight (HMW) adiponectin. Stepwise regression analysis was done with forward selection of variables, including age, FPG, HOMA-IR, TG, HDL cholesterol, uric acid, GGT, C-reactive protein, and HMW adiponectin. In a model that explained 57.5% of the variation of the peak sCD26/DPP4 level, GGT (β = 0.382, P = 0.007) and HOMA-IR (β = 0.307, P = 0.034) were independent determinants of the peak serum level of sCD26/DPP4. Serum HMW adiponectin decreased significantly from 4.43 μg/mL (interquartile range, from 2.80 to 6.65 μg/mL) at baseline to 4.17 μg/mL (interquartile range, from 2.48 to 6.96 μg/mL) 120 minutes after the oral glucose load (P < 0.0001). The baseline serum level of sCD26/DPP4 showed a significant negative correlation with the percent change of HMW adiponectin during the OGTT. In conclusion, the serum level of sCD26/DPP4 increased acutely after an oral glucose load in apparently healthy subjects. The abrupt increase of serum sCD26/DPP4 after a glucose load may be a marker of insulin resistance that could come from liver or muscle., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Adverse outcome pathways (AOPs) are novel tools in toxicology and human risk assessment with broad potential. AOPs are designed to provide a clear-cut mechanistic representation of critical toxicological effects that span over different layers of biological organization. AOPs share a common structure consisting of a molecular initiating event, a series of intermediate steps and key events, and an adverse outcome. Development of AOPs ideally complies with OECD guidelines. This also holds true for AOP evaluation, which includes consideration of the Bradford Hill criteria for weight-of-evidence assessment and meeting a set of key questions defined by the OECD. Elaborate AOP frameworks have yet been proposed for chemical-induced skin sensitization, cholestasis, liver fibrosis and liver steatosis. These newly postulated AOPs can serve a number of ubiquitous purposes, including the establishment of (quantitative) structure-activity relationships, the development of novel in vitro toxicity screening tests and the elaboration of prioritization strategies., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Inverse correlations of high serum bilirubin with metabolic and cardiovascular disease have been suggested. However, anti-atherogenic effects of bilirubin have not been well-established in terms of the presence of plaques and stenosis identified in coronary computed tomography (CT)., Methods: A cross-sectional study was conducted on 2862 men who were free of cardiovascular disease and underwent coronary CT as part of a routine medical screening examination. Coronary stenotic lesions were considered to be incidences of coronary atherosclerosis, and stenosis was classified as stenosis <50% or ≥50%, according to degree of stenosis., Results: The prevalences of coronary atherosclerosis and stenosis ≥50% in subjects with elevated bilirubin levels (>1.2 mg/dL) were lower than those in subjects with normal bilirubin levels (≤1.2 mg/dL) (19.9% vs. 27.9%, p < 0.001, 8.5% vs. 10.3%, p = 0.044). Bilirubin was inversely associated with total plaques (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.48-0.73 in the 4th quartile vs. 1st quartile) and calcified plaques (OR 0.60, 95% CI 0.49-0.75) in univariate analysis. After adjusting for traditional risk factors, it was found that coronary atherosclerosis (OR 0.73, 95% CI 0.56-0.94 in the 4th quartile vs. 1st quartile) and calcified plaque (OR 0.66, 95% CI 0.53-0.84) were inversely associated with the bilirubin grade in a dose-dependent manner., Conclusions: The serum bilirubin level was inversely associated with coronary atherosclerosis and calcified plaques in a dose-dependent manner. These results suggested that serum bilirubin could be used as a protective biomarker of coronary artery disease., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Commutability is an essential requirement for control materials used in external quality assessment schemes. Testing control materials for commutability requires costly and time-consuming experiments. The aim of our work was the validation of a more effective way to evaluate commutability., Methods: Commutability of two control materials for gamma-glutamyltransferase (GGT) activity between IFCC reference method and four routine methods (Abbott, IL, Roche, Siemens) was tested with the conventional approach and with a new one. The new approach consisted in assessing the effects on the two controls and on two human serum pools, of similar GGT concentrations, of modifications of the measurement conditions (pH, substrate and buffer concentration). The effects of these variations on the two types of materials were compared., Results: Low GGT activity control was commutable in all method comparisons, the high level control was non-commutable for Abbott and Roche. Both controls showed behavior different from human pools when changing the measurement conditions, but this fact had significant effects only for the conditions of Abbott and Roche methods, confirming the results of the conventional approach., Conclusions: The proposed approach seems able to identify the reasons for non-commutability and to anticipate the final commutable or non-commutable behavior of the material., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background & Aims: Disease progression in non-alcoholic fatty liver disease (NAFLD) is not well understood and there is controversy about whether non-alcoholic fatty liver (NAFL, i.e., steatosis alone or with mild inflammation not qualifying for steatohepatitis) can evolve towards steatohepatitis (NASH) with fibrosis., Methods: We reviewed 70 patients with untreated NAFLD and with two biopsies performed more than one year apart. Clinical and biological data were recorded at the time of both biopsies. Alcohol consumption did not change during follow-up., Results: Initially 25 patients had NAFL and 45 had NASH and/or advanced fibrosis. After a mean follow-up of 3.7 years (s.d. 2.1), 16 NAFL patients developed NASH, eight with severe ballooning and six with bridging fibrosis on the follow-up biopsy. Patients with mild lobular inflammation or any degree of fibrosis were at higher risk of progression than those with steatosis alone. Those with unambiguous disease progression were older and had worsening of their metabolic risk factors (higher weight and more diabetes at baseline and during follow-up). In the whole cohort, ballooning progression and bridging fibrosis often occurred together and co-existed with a reduction in ALT, higher weight gain, and a higher incidence of diabetes during follow-up., Conclusions: A substantial proportion of patients with NAFL can progress towards well-defined NASH with bridging fibrosis, especially if metabolic risk factors deteriorate. Even mild inflammation or fibrosis could substantially increase the risk of progression when compared to steatosis alone. Current monitoring practices of these patients should be revised., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: The exact mechanisms behind the association between atherosclerosis and gamma-glutamyltransferase (GGT) are unclear. Coronary artery calcification (CAC) detected by computerized tomography is an important marker of atherosclerosis and its severity correlates with coronary plaque burden. The aim of this study was to investigate if serum GGT levels are associated with CAC in patients without known coronary heart disease (CHD) who had low-intermediate risk for CHD., Methods: Two hundred and seventy two patients who had low-intermediate risk for coronary artery disease were included in the study. Serum GGT levels were measured spectrophotometrically. CACS (Agatston method) were performed using a 64-slice computerized tomography scanner. The patients were grouped according to their GGT values in four quartiles., Results: Patients in higher GGT quartiles had elevated CAC score (P<0.001). Patients in higher GGT quartiles were predominantly males (P<0.001) and were more likely to be smoking (P=0.004), and have elevated uric acid (P<0.001), fasting blood glucose (P<0.001), CRP levels (P=0.003) and 10-year total cardiovascular risk (P=0.007) and low HDL levels (P<0.001). Positive correlations were found between log GGT and CAC (r=0.233, P<0.001). In the multivariate analysis GGT, age, smoking and serum uric acid levels appeared as independent factors predictive of presence of CAC., Conclusions: We demonstrated a significant correlation between serum GGT levels and CAC and CHD risk factors. Serum GGT level was an independent marker of CAC., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background & Aims: Vitamin D deficiency has been frequently reported in advanced liver disease. However, its influence on alcoholic liver disease (ALD) has been poorly elucidated. We investigated the association of vitamin D with clinical, biological, and histological parameters and survival in ALD patients. Furthermore, we explored the effect of vitamin D treatment on ALD patient peripheral blood mononuclear cells (PBMCs), and in a murine experimental model of ALD., Methods: Serum levels of 25-hydroxyvitamin D [25(OH)D] were determined in 324 Caucasian ALD patients and 201 healthy controls. In vitro experiments on vitamin D pre-treated PBMCs evaluated TNFα production by ELISA in culture supernatants. Mice were submitted to an ethanol-fed diet and some of them were orally supplemented three times per week with 1,25(OH)2D., Results: Severe deficiency in 25(OH)D (<10 ng/ml) was significantly associated with higher aspartate aminotransferase levels (p=1.00 × 10(-3)), increased hepatic venous pressure gradient (p=5.80 × 10(-6)), MELD (p=2.50 × 10(-4)), and Child-Pugh scores (p=8.50 × 10(-7)). Furthermore, in multivariable analysis, a low 25(OH)D concentration was associated with cirrhosis (OR=2.13, 95% CI=1.18-3.84, p=0.013) and mortality (HR=4.33, 95% CI=1.47-12.78, p=7.94 × 10(-3)) at one year. In addition, in vitro, 1,25(OH)2D pretreatment decreased TNFα production by stimulated PBMCs of ALD patients (p=3.00 × 10(-3)), while in vivo, it decreased hepatic TNFα expression in ethanol-fed mice (p=0.04)., Conclusions: Low 25(OH)D levels are associated with increased liver damage and mortality in ALD. Our results suggest that vitamin D might be both a biomarker of severity and a potential therapeutic target in ALD., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: Serum γ-glutamyltranspeptidase (GGT), a marker of fatty liver disease (FLD), predicts mortality in young adults. However, the association between serum GGT and mortality in older adults is unclear., Objectives: To examine if elevated serum GGT predicts all-cause, cardiovascular (CVD), and liver mortality in community-dwelling older adults., Design and Setting: A prospective cohort study including 2364 participants (mean-age 70 yr, BMI-24.5 kg/m 2 , 54% women) from the Rancho Bernardo Study who attended a research visit in 1984-87 when multiple metabolic covariates were ascertained including serum GGT. They were followed for a mean (± standard deviation) of 13.7 (±6.2) years., Measurement: Multivariable-adjusted Cox-proportional hazards analyses were conducted to examine the association between elevated serum GGT (>51 U/L in men and > 33 U/L in women) and all-cause, CVD, and liver mortality., Results: In these older men and women, cumulative mortality was 56.2% (n=1329) with CVD and liver mortality accounting for 49.4% and 2.3% of all deaths, respectively, over 32,387 person-years of follow-up. In multivariate analyses (adjusted for age, sex, alcohol use, body-mass-index, total cholesterol, HDL cholesterol, serum triglyceride, smoking status, systolic blood pressure, diabetes mellitus, serum interleukin-6, and c-reactive protein), serum GGT elevation was significantly associated with all-cause (HR, 1.55, 95% CI, 1.21-1.98), CVD (HR, 1.51, 95% CI, 1.04-2.17), and liver mortality (HR, 9.10, 95% CI, 3.42-24.26)., Conclusions: In community-dwelling older adults, serum GGT is an independent predictor of all-cause, CVD, and liver mortality.