Higher Gamma-glutamyl Transpeptidase Levels Research Articles

Sex difference in the associations among liver function parameters with incident diabetes mellitus in a large Taiwanese population follow-up study.

The prevalence of diabetes mellitus (DM) in Taiwan between 2017 and 2020 was 11.05%, which is higher than the global prevalence (10.5%). Previous studies have shown that patients with DM have higher liver enzyme levels than those without DM. However, it is unclear whether there are sex differences in the association between incident DM and liver function. Therefore, the aim of this longitudinal study was to investigate this issue in a large Taiwanese cohort. We identified 27,026 participants from the Taiwan Biobank, and excluded those with baseline DM (n = 2,637), and those without follow-up data on DM, serum fasting glucose or glycosylated hemoglobin A1c (n = 43). The remaining 24,346 participants (male: 8,334; female: 16,012; mean age 50.5 ± 10.4 years) were enrolled and followed for a median of 4 years. Of the enrolled participants, 1,109 (4.6%) had incident DM and 23,237 (95.4%) did not. Multivariable analysis showed that high levels of glutamic-oxaloacetic transaminase (AST) (p < 0.001), glutamic-pyruvic transaminase (ALT) (p < 0.001), albumin (p = 0.003), α-fetoprotein (p = 0.019), and gamma-glutamyl transpeptidase (GGT) (p = 0.001) were significantly associated with incident DM in the male participants. In comparison, high levels of AST (p = 0.010), ALT (p < 0.001), albumin (p = 0.001) and GGT (p < 0.001), and low total bilirubin (p = 0.001) were significantly associated with incident DM in the female participants. There were significant interactions between total bilirubin and sex (p = 0.031), and GGT and sex (p = 0.011) on incident DM. In conclusion, liver function parameters were significantly associated with incident DM. Further, there were differences in the associations between the male and female participants.

Factors associated with the development of extrahepatic malignancy in patients with nonalcoholic fatty liver disease: a single-center longitudinal study.

The aim of the present study was to determine incident cases of extrahepatic malignancy in patients with nonalcoholic fatty liver disease (NAFLD) and to identify whether the factors are associated with cancer development. Between 15 January 2001 and 14 March 2021, a total of 1365 patients had been diagnosed with NAFLD were enrolled in the study. The median follow-up period was 59.5 months. The mean age was 50.9 ± 10.9 years. The female gender was predominant (57%). During the follow-up period, 62 extrahepatic malignancies and 11 hepatocellular carcinomas were identified. Of all extrahepatic malignancies, 51 were solid organ malignancies and 11 were hematological malignancies. Female breast cancer was the most frequent (25.8%), followed by thyroid cancer (19.4%), lymphoma (12.9%), and lung cancer (9.7%). In univariate and multivariable analyses, after adjusting for age and sex, the presence of diabetes and high initial baseline gamma glutamyl transpeptidase (GGT) levels were significantly associated with the development of extrahepatic malignancies [hazard ratio (HR) = 1.82, 95% confidence interval (CI): 1.04-3.20, P = 0.036] and HR = 1.96, 95% CI: 1.14-3.38, P = 0.015, respectively). In 424 biopsy-proven NAFLD patients, the development of extrahepatic cancer was significantly associated with the severity of hepatic fibrosis (HR = 3.31, 95% CI: 1.36-8.07; P = 0.008). Extrahepatic malignancies are frequently seen in patients with NAFLD. Diabetes mellitus, high baseline GGT levels, and significant hepatic fibrosis are associated with the development of extrahepatic cancer in patients with NAFLD.

Gut microbiome is associated with metabolic syndrome accompanied by elevated gamma-glutamyl transpeptidase in men.

It is predicted that by 2035, metabolic syndrome (MS) will be found in nearly more than half of our adult population, seriously affecting the health of our body. MS is usually accompanied by the occurrence of abnormal liver enzymes, such as elevated gamma-glutamyl transpeptidase (GGT). More and more studies have shown that the gut microbiota is involved in MS; however, the correlation between gut microbiota and MS with elevated GGT has not been studied comprehensively. Especially, there are few reports about its role in the physical examination of the population of men with MS and elevated GGT. By using the whole-genome shotgun sequencing technology, we conducted a genome-wide association study of the gut microbiome in 66 participants diagnosed as having MS accompanied by high levels of GGT (case group) and 66 participants with only MS and normal GGT level (control group). We found that the number of gut microbial species was reduced in participants in the case group compared to that of the control group. The overall microbial composition between the two groups is of significant difference. The gut microbiota in the case group is characterized by increased levels of “harmful bacteria” such as Megamonas hypermegale, Megamonas funiformis, Megamonas unclassified, Klebsiella pneumoniae, and Fusobacterium mortiferum and decreased levels of “beneficial bacteria” such as Faecalibacterium prausnitzii, Eubacterium eligens, Bifidobacterium longum, Bifidobacterium pseudocatenulatum, Bacteroides dorei, and Alistipes putredinis. Moreover, the pathways of POLYAMSYN-PWY, ARG+POLYAMINE-SYN, PWY-6305, and GOLPDLCAT-PWY were also increased in the case group, which may play a role in the elevation of GGT by producing amine, polyamine, putrescine, and endogenous alcohol. Taken together, there are apparent changes in the composition of the gut microbiome in men with MS and abnormal GGT levels, and it is high time to discover specific gut microbiome as a potential therapeutic target in that population. More in-depth studies of relevant mechanism could offer some new methods for the treatment of MS with elevated GGT.

Association Between Gamma-Glutamyl Transferase, Total Bilirubin and Systemic Lupus Erythematosus in Chinese Women.

BackgroundSystemic lupus erythematosus (SLE) affects many organs and systems of the human organism, at present, its specific pathogenesis is not completely clear, but inflammation is considered to be an important factor involved in the pathogenesis and progression of SLE. Gamma-glutamyl transpeptidase (GGT) and total bilirubin (TBIL) have different effects on inflammation: GGT has pro-inflammatory effects, on the contrary, TBIL has anti-inflammatory effects. Study has found that GGT and TBIL play opposite roles in metabolic diseases. However, the roles of them in SLE are unknown. Meanwhile, the relationship between GGT and SLE also remains unexplored.MethodWe recruited 341 SLE patients and 332 healthy individuals in Liaocheng People’s Hospital from August 2018 to May 2019. We diagnosed SLE using 2019 revised American College of Rheumatology (ACR) SLE criteria, and modeled the study outcomes using logistic regression to explore the respective relationship between GGT, TBIL and SLE. We also analyzed the interaction of GGT and TBIL in the progression of SLE.ResultsWe found that the levels of CRP, IL-6 and TNF-α in the aggravated group were significantly higher than those in the unaggravated group, the levels of C3 and C4 in the aggravated group were significantly lower than those in the unaggravated group. According to Spearman correlation analysis, GGT is proportional to CRP (rs=0.417) and IL-6 (rs=0.412), inversely proportional to C3 (rs=-0.177) and C4 (rs=0.-132). TBIL was inversely proportional to CRP (rs=-0.328) and TNF(rs=-0.360), and positively proportional to C3 (rs=0.174) and C4 (rs=0.172). In the fully adjusted model, compared to the lowest quartile, the highest quartile of GGT exhibited a positive association with the risk of SLE aggravation (OR=2.99, 95% CI: 1.42–6.31, P<0.001). At the same time, compared to the highest quartile, the quartile lowest of TBIL exhibited a positive association with the risk of SLE aggravation (OR=2.66, 95% CI: 1.27–5.59, P<0.001) in the fully adjusted model. Through interaction analysis, we found that women with high GGT levels had an increased risk of SLE aggravation when they had a low level of TBIL (OR=3.68, 95% CI: 1.51–9.01, for women with Q1 TBIL and Q4 GGT compared to women with Q2-Q4 TBIL and Q1-Q3 GGT, P for interaction <0.001), the combined AUC value (AUCCOMBINED=0.711) of high GGT level and TBIL were higher than their respective values (AUCGGT=0.612, AUCTBIL=0.614).ConclusionWe found that the effects of GGT and TBIL in the progression of SLE are opposite. High GGT level might be a risk factor for SLE aggravation, as GGT levels increased, so did the risk of SLE aggravation. At the same time, we found that low TBIL level might be a risk factor for SLE aggravation. Moreover, high GGT level and low TBIL level had a subadditive effect on the increased risk of SLE aggravation.

Composition of Dietary Fatty Acids and Health Risks in Japanese Youths.

In the overall composition of dietary fatty acids (FAs), the quantity of each FA is interrelated with that of others. We examined the associations between dietary FA composition and cardiometabolic risk in Japanese youths. Risk factors (anthropometric characteristics, serum lipid and liver enzyme levels, and blood pressure) were measured in 5485 junior-high-school students. Dietary intake was assessed using a food frequency questionnaire. The mean saturated FA (SFA), monounsaturated FA (MUFA), omega-6 polyunsaturated FAs (PUFAs), and omega-3 PUFAs intake were 9.6%E, 10.3%E, 6.3%E, and 1.1%E, respectively. In compositional regression analysis controlled for confounders, a high intake of omega-6 PUFAs relative to others was associated with low low-density-lipoprotein cholesterol levels (LDL-C; p = 0.003), and relative SFA intake was associated with high levels of gamma-glutamyl transpeptidase (p = 0.019). Relative omega-3 PUFAs intake was associated with low blood pressure (p = 0.005–0.034) but had unfavorable effects on adiposity and alanine transaminase. Substitutional models showed similar results for omega-6 PUFAs on LDL-C, but MUFA had inconsistent effects on risk factors. The results from the compositional data analysis were consistent with previous studies and clinical practice/knowledge. Focusing on increasing omega-6 PUFAs in Japanese youths could have favorable consequences in the long term.

Serum Levels of Glutamate-Pyruvate Transaminase, Glutamate-Oxaloacetate Transaminase and Gamma-Glutamyl Transferase in 1494 Patients with Various Genotypes for the Alpha-1 Antitrypsin Gene

Background: Patients with liver disease associated with alpha-1 antitrypsin deficiency (AATD) are homozygous for the Z mutation, leading to chronic liver damage. Objective: To assess the serum levels of glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase (GPT), and gamma-glutamyl transpeptidase (GGT) in patients with different genotypes for the alpha-1 antitrypsin (AAT) gene. Methods: Patients (n = 1494) underwent genotyping of the SERPINA1 gene, together with a determination of AAT and GOT and GPT and GGT transaminase levels. Patients with a deficient allele (n = 476) and with a normal genotype were compared. Results: A statistically significant association was found between deficient genotypes and GOT (p < 0.0003), GPT (p < 0.002), and GGT (p < 0.006). Comparing GOT levels in patients with PI*Z deficient variant versus those with normal genotype, an odds ratio (OR) of 2.72 (CI: 1.5–4.87) (p < 0.0005) was obtained. This finding was replicated with the PI*Z allele and the GPT values (OR = 2.31; CI: 1.45–3.67; p < 0.0003). In addition, a statistically significant association was found between liver enzymes and AAT values. Conclusion: The PI*Z allele seemed to be a risk factor for the development of liver damage. AAT deficient genotypes were associated with GOT, GPT, and GGT altered values. Low AAT levels were associated with high GPT and GGT levels.

Blood parameters in fetuses infected with cytomegalovirus according to the severity of brain damage and trimester of pregnancy at cordocentesis

Background and objectiveCytomegalovirus (CMV) remains a major cause of congenital infection and disease. During pregnancy, symptomatic cases can be detected through ultrasound (US) features, nevertheless, prognostic assessment is difficult. The aim of this study was to assess the predictive value of specific blood parameters in CMV infected fetuses. Study designTwenty-eight CMV-infected fetuses in which a cordocentesis had been performed were included. Fetuses were considered severely or mildly affected according to prenatal US/MRI brain damage. Fetal blood parameters were assessed for the prediction of severe brain abnormalities, and compared according to the trimester of pregnancy. Logistic regression and receiver operating curve analysis were performed. ResultsThrombocytopenia (≤100,000/mm3; p:0.03) and high levels of gamma-glutamyl transpeptidase (GGT) (≥151 IU/L; p:0.02) signaled severity. For the prediction of brain damage, GGT levels ≥ 183 UI/l achieved 71% sensitivity, 83% specificity (AUC: 0.78), and OR of 2.05 (95% CI: 1.22–3.43) per 100 IU/l increase, adjusted for gestational age. However, thrombocytopenia (91% vs 50%; p: 0.04), β2 microglobulin >10.4 mg/l (60% vs 0% p: 0.03), CMV-DNA >50,000 copies/ml (80% vs 25%; p: 0.02), and positive IgM (70% vs 17%; p: 0.04) were observed significantly more often in severely damaged fetuses sampled ≤28 weeks than thereafter. ConclusionIn CMV infected fetuses, thrombocytopenia and high levels of GGT are associated with severe US/MRI brain abnormalities. Nevertheless, among severely affected fetuses, blood parameters, with exception of GGT, change according to gestational age. Fetal blood could be less predictive of brain damage in the third trimester.

Genetic variation in the microsomal triglyceride transfer protein (\u2212493G/T) is associated with hepatic steatosis in patients infected with hepatitis C virus

BackgroundIn chronic hepatitis C, the fibrosis progression rates are extremely variable and can be influenced by factors associated with the host, virus and environment. Among the associated metabolic factors, hepatic steatosis is characterized by an accumulation of triglycerides in hepatocytes. In the host, genetic determinants of hepatic steatosis are observed, such as single-nucleotide polymorphisms (SNPs) in the microsomal triglyceride transfer protein (MTTP) gene. The MTTP -493G/T SNP appears to play an important role in the regulation of gene expression and influences the plasma concentration of circulating low-density lipoprotein (LDL). The present study investigated the influence of this SNP in the development of hepatic steatosis in patients with chronic hepatitis C and evaluated the association of hepatic steatosis with certain characteristics of these patients and the hepatitis C virus (HCV).MethodsTwo hundred thirty-nine patients with chronic hepatitis C were genotyped for the MTTP -493G⁄T SNP by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The association between hepatic steatosis and selected characteristics of the patient and virus was evaluated using bivariate and multivariate analyses.ResultsThe most prevalent MTTP -493G/T genotype was GG (46%) followed by GT (43.5%) and TT (10.5%). Multivariate analysis of the total cohort revealed associations between the presence of hepatic steatosis and inflammatory activity of moderate to high intensity (P < 0.001), advanced age (P = 0.010), elevated gamma glutamyl transpeptidase (GGT) levels (P = 0.010) and low LDL levels (P = 0.022). Hepatic steatosis was also associated with the TT/GT genotype of the MTTP -493G⁄T SNP in patients infected with HCV genotype 3 (P < 0.001).ConclusionsIn chronic hepatitis C patients infected with HCV genotype 3 and with the TT/GT genotype of the MTTP -493G/T SNP, a significant increase in hepatic steatosis was observed, which may indicate that this SNP has a significant influence on the accumulation of triglycerides in hepatocytes. Furthermore, associations were observed between hepatic steatosis and inflammatory activity of moderate to high intensity, advanced age, elevated GGT and low LDL levels.

Tumor and serum gamma-glutamyl transpeptidase, new prognostic and molecular interpretation of an old biomarker in gastric cancer.

BackgroundGastric Cancer is one of the most lethal malignancies worldwide. Gamma-glutamyl transpeptidase (GGT) is an enzyme mainly involved in cellular glutathione homeostasis. We aim to explore the clinical value of GGT in gastric cancer.ResultsAmong 322 patients enrolled, 65/82 patients were determined as GGT positive in serum/tumor, respectively. High tumor GGT expression is significantly associated with lymph node metastasis, histological subtype, and Her2 expression. Kaplan-Meier curve shows that high tumor GGT patients have shorter overall survival (P log-rank=0.001) and progress-free survival (P log-rank =0.001). Patients with both high tumor and serum GGT have the poorest prognosis. The multivariable Cox analysis shows that the hazard ratio of overall survival for high tumor GGT is 1.69 (95% CI 1.19-2.37). High serum GGT is a poor prognostic factor in adjuvant chemotherapy hazard ratio=2.18, 95%CI (1.15-4.47). These findings were further validated in six online datasets. Gene Sets Enrichment Analysis showed that GGT promotes cancer progression through EMT, KRAS, SRC and PKCA pathways.MethodsTumor GGT and serum GGT levels were evaluated with immuno-histochemistry staining and enzymatic assay, respectively. Kaplan-Meier curve and Cox regression model were used to test the association between GGT and gastric cancer prognosis. Independent datasets from Gene Expression Omnibus and Gene Sets Enrichment Analysis were applied to validate the findings and explore the potential mechanisms.ConclusionBoth tumor GGT and serum GGT are poor prognostic factors in gastric cancer. Patients with high tumor and serum GGT levels require more intense treatment and follow-up.

P335 Prevalence and risk factors for non alcoholic fatty liver disease in inflammatory bowel disease

Background: Non alcoholic fatty liver disease (NAFLD) is responsible for up to 40% of hepatic alterations diagnosed in inflammatory bowel diseases (IBD). We aimed to evaluate the prevalence and risk factors for NAFLD in a large cohort of IBD patients and the stage of liver fibrosis by transient elastography (TE). Methods: This study included consecutive patients affected by Crohn's disease (CD) or ulcerative colitis (UC), referred to our tertiary centre for IBD from December 2015 to July 2016. Patients with previous diagnosis of chronic liver disease with different etiology from NAFLD, daily alcohol consumption higher than 20 g in women and 30 g in men or conditions affecting the execution of TE were excluded. Data regarding IBD characteristics and liver laboratory tests were collected. The markers of metabolic syndrome were analyzed. All subjects underwent an abdominal ultrasonography to estimate presence/degree of steatosis and TE to measure liver stiffness (LS). An age and sex-matched group of controls was recruited. Student's t or Chi-squared tests were used where indicated. For multivariate analysis, multinomial logistic regression was used to determine which factors could have influenced the presence of NAFLD. Results: NAFLD was observed in 106 out of 378 (28%) patients with IBD and in 33 (20.1%) of 162 controls (p=0.04). The prevalence of diabetes and abdominal excessive adiposity was higher for IBD than controls. Patients with NAFLD were more frequently male, young and affected by diabetes, hypertension and insulin resistance. Their mean waist circumference and BMI were higher in NAFLD compared to non-NAFLD patients. Additionally, NAFLD subjects showed higher levels of transaminases and gamma-glutamyltranspeptidase, HDL cholesterol, triglycerides and fasting blood glucose. Finally, their mean LS was higher than in non-NAFLD patients. At multivariate analysis the risk of NAFLD in IBD was directly correlated to insulin resistance (odd ratio OR=14.73 p<0.0001), high waist circumference (OR=4.85 p=0.04), high BMI (OR=1.6 p=0.01), high gamma-glutamyltranspeptidase level (OR=3.9 p=0.04) and high fasting blood glucose (OR=1.3 p=0.04). Detailed aspects of our analysis are reported in the table. Table 1. Comparison between controls and IBD Conclusions: Despite NAFLD is an increasing problem in IBD, it seems to be correlated to the presence of metabolic syndrome rather than to IBD characteristics.

Value of Gamma-Glutamyl Transpeptidase for Diagnosis of Biliary Atresia by Correlation With Age.

The aim of the study was to analyze the value of gamma-glutamyl transpeptidase (GGT) for distinguishing biliary atresia (BA) from non-BA for patients suspected of having neonatal obstructive jaundice by correlation with age. From January 2003 to March 2014, cholangiography and/or surgical exploration were undertaken in 1469 patients with suspicion of having neonatal obstructive jaundice. A total of 1338 patients were diagnosed with BA intraoperatively. Preoperative medical records were compared between BA and non-BA patients. Preoperative levels of total bilirubin, direct bilirubin, and GGT were significantly higher in the BA group (P < 0.05), whereas the non-BA group had higher alkaline phosphatase levels (P = 0.0003). The area under the receiver operating characteristic curve of total bilirubin, direct bilirubin, GGT, and alkaline phosphatase was 0.584, 0.614, 0.843, and 0.398, respectively. In all age groups (i: 31-60 days; ii: 61-90 days; iii: 91-120 days; iv: ≥121 days), BA groups had higher GGT levels (in IU/L) (i: 725.3 ± 549.9; ii: 927.0 ± 679.8; iii: 1114.3 ± 823.1; iv: 767.5 ± 666.7). The level of GGT in patients with BA younger than 30 days was 834.2 ± 475.3 IU/L. GGT levels had the highest diagnostic value (0.869) in group ii (61-90 days) and the lowest diagnosis value (0.712) in group iv (≥121 days). At a cutoff of >303 IU/L in group ii (61-90 days), GGT had 82.8% sensitivity and 81.6% specificity for the discrimination of BA. GGT levels contribute to the diagnosis of BA before 120 days. Age must be considered if using GGT levels as a diagnostic test for BA.

Toll-like receptor 3 gene polymorphisms are not associated with the risk of hepatitis B and hepatitis C virus infection.

The present study investigated the prevalence of two single-nucleotide polymorphisms (SNPs) in the Toll-like receptor 3 (TLR3) gene in patients infected with hepatitis B virus (HBV) and hepatitis C virus (HCV). Samples collected from HCV (n = 74) and HBV (n = 35) carriers were subjected to quantitative real-time PCR (qPCR) to detect the presence of the SNPs rs5743305 and rs3775291 in TLR3 and to measure the following biomarkers: alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), and prothrombin time (PT). A healthy control group was investigated and consisted of 299 HCV- and HBV-seronegative individuals. No significant differences in allele, genotype and haplotype frequencies were observed between the investigated groups, and no association was observed between the polymorphisms and histopathological results. Nevertheless, genotypes TA/AA (rs5743305) and GG (rs3775291) appear to be associated with higher levels of ALT (p<0.01), AST (p<0.05) and PT (p<0.05). In addition, genotypes TT (rs5743305; p<0.05) and GG (rs3775291; p<0.05) were associated with higher GGT levels. This genetic analysis revealed the absence of an association between the polymorphisms investigated and susceptibility to HBV and HCV infection; however, these polymorphisms might be associated with a greater degree of biliary damage during the course of HCV infection.

Low alpha-fetoprotein HCC and the role of GGTP.

HCC patients are heterogeneous in terms of both tumor and liver factors. Alpha-fetoprotein (AFP) is an important prognostic tumor marker for those patients with elevated AFP levels. To examine the differences in HCC patients with high or low AFP levels in blood and evaluate the prognostic parameters in low AFP patients. A cohort of 2,440 HCC patients from 11 Italian medical centers was studied. AFP-positive patients were compared to AFP-negative ones, and the blood and tumor parameters of AFP-negative patients were examined. Low blood AFP levels were found in 58% of the total cohort, in 64% of patients with small HCCs, and in 51% of patients with large HCCs. In patients with large tumors, platelet and gamma glutamyl transpeptidase (GGTP) levels, tumor multifocality and portal vein thrombosis (PVT) incidence were all greater than in patients with small tumors, regardless of AFP status. Patients with higher AFP levels had worse survival rates than those with low AFP in each tumor size group. In patients with small tumors, the elevated AFP was associated with significantly increased PVT and worse survival. In patients with large tumors, the elevated AFP was associated with significantly higher GGTP, ALKP, and bilirubin levels, as well as with increased PVT and multifocality, and worse survival. Low-AFP patients with high GGTP levels had worse survival than patients with low GGTP levels. Patients with low AFP were the majority in this cohort, and patients with elevated GGTP had worse prognosis than those with low GGTP. GGTP may be a useful tumor and prognosis marker in low-AFP patients. AFP-negative patients are important to identify due to their enhanced survival.

Significance of Platelet and AFP Levels and Liver Function Parameters for HCC Size and Survival

Hepatocellular carcinoma (HCC) is a heterogeneous disease with both tumor and liver factors being involved. To investigate HCC clinical phenotypes and factors related to HCC size. Prospectively-collected HCC patients' data from a large Italian database were arranged according to the maximum tumor diameter (MTD) and divided into tumor size terciles, which were then compared in terms of several common clinical parameters and patients' survival. An higer MTD tercile was significantly associated with increased blood alpha-fetoprotein (AFP), gamma-glutamyl transpeptidase (GGTP), and platelet levels. Patients with higher platelet levels had larger tumors and higher GGTP levels, with lower bilirubin levels. However, patients with the highest AFP levels had larger tumors and higher bilirubin levels, reflecting an aggressive biology. AFP correlation analysis revealed the existence of 2 different groups of patients: those with higher and with lower AFP levels, each with different patient and tumor characteristics. The Cox proportional-hazard model showed that a higher risk of death was correlated with GGTP and bilirubin levels, tumor size and number, and portal vein thrombosis (PVT), but not with AFP or platelet levels. An increased tumor size was associated with increased blood platelet counts, AFP and GGTP levels. Platelet and AFP levels were important indicators of tumor size, but not of survival.

Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: A propensity score analysis

Some patients with chronic hepatitis B virus (HBV) infection progress to hepatocellular carcinoma (HCC). However, the long-term effect of nucleos(t)ide analogue (NA) therapy on progression to HCC is unclear. Therefore, we compared chronic hepatitis B patients who received NA therapy to those who did not, using a propensity analysis. Of 785 consecutive HBV carriers between 1998 and 2008, 117 patients who received NA therapy and 117 patients who did not, were selected by eligibility criteria and propensity score matching. Factors associated with the development of HCC were analyzed. In the follow-up period, HCC developed in 57 of 234 patients (24.4%). Factors significantly associated with the incidence of HCC, as determined by Cox proportional hazards models, include higher age (hazard ratio, 4.36 [95% confidence interval, 1.33-14.29], p=0.015), NA treatment (0.28 [0.13-0.62], p=0.002), basal core promoter (BCP) mutations (12.74 [1.74-93.11], p=0.012), high HBV core-related antigen (HBcrAg) (2.77 [1.07-7.17], p=0.036), and high gamma glutamyl transpeptidase levels (2.76 [1.49-5.12], p=0.001). NA therapy reduced the risk of HCC compared with untreated controls. Higher serum levels of HBcrAg and BCP mutations are associated with progression to HCC, independent of NA therapy.

Abstract P005: Traditional Cardiovascular Risk Factors Explain the Association Between GGT and Incident Cardiovascular Events, but not Total Mortality

Background: Elevated levels of the liver enzyme gamma glutamyl transpeptidase (GGT) are associated with incident diabetes and the metabolic syndrome, but there is conflicting evidence regarding the association between GGT and cardiovascular risk. Hypothesis: GGT is positively associated with risk of coronary heart disease (CHD), congestive heart failure (CHF), and total mortality, independently of metabolic factors. Methods: We analyzed data from 9,104 participants in the Atherosclerosis Risk in Communities (ARIC) Study without cardiovascular disease or high alcohol consumption (&gt;2 drinks per day for women and &gt; 1 drink per day for men) at baseline (Visit 4, 1996-1999). GGT was measured from thawed plasma samples from Visit 4. The primary outcome was incident CHD (non-fatal MI, coronary revascularizations, or CHD death). Secondary outcomes were CHF and total mortality. We estimated the hazard ratios from Cox models for the risks associated with quartiles of GGT and ln-transformed GGT. Results: During a median of 10 years of follow-up, there were 925 CHD events, 654 CHF events, and 1,084 deaths. Male gender, diabetes, and components of the metabolic syndrome were associated with higher GGT levels at baseline. GGT was positively associated with risk of CHD and CHF in age-adjusted models, but not after adjustment for components of the metabolic syndrome and diabetes ( Table ). In contrast, the highest quartile of GGT remained associated with total mortality even after adjustment for all metabolic factors. Similar findings were seen for analyses of ln-GTT. Conclusion: The association between GGT and incident cardiovascular events was largely explained by metabolic risk factors. However, elevated GGT was associated with total mortality independent of the metabolic syndrome and diabetes, suggesting a potential alternative mechanism of risk. Table Hazard Ratios of Incident CHD, CHF and Total Mortality Associated with Quartiles * of GGT GGT Q1 (≤14 U/L)n=2,039) GGT Q2 (15-20 U/L)n=2,301 GGT Q3 (21-30 U/L)n=2,385 GGT Q4 (≥31 U/L)n=2,379 CHD Model 1 Ref 1.16(0.93-1.44) 1.28(1.04-1.58) 1.62(1.32-1.99) Model 2 Ref 1.10(0.89-1.37) 1.18(0.95-1.47) 1.47(1.19-1.82) Model 3 Ref 1.03(0.82-1.28) 1.06(0.85-1.32) 1.30(1.04-.1.61) Model 4 Ref 1.00(0.80-1.24) 1.00(0.80-1.24) 1.17(0.94-1.46) CHF Model 1 Ref 1.12(0.86-1.45) 1.36(1.06-1.74) 1.97(1.55-2.51) Model 2 Ref 1.00(0.77-1.29) 1.12(0.87-1.45) 1.59(1.24-2.02) Model 3 Ref 0.96(0.74-1.24) 1.04(0.80-1.35) 1.41(1.09-1.81) Model 4 Ref 0.90(0.70-1.18) 0.93(0.71-1.20) 1.17(0.91-1.51) TOTAL MORTALITY Ref 0.90(0.69-1.17) 0.94(0.72-1.22) 1.13(0.87-1.46) Model 1 Ref 1.14(0.94-1.38) 1.16(0.96-1.41) 1.52(1.26-1.83) Model 2 Ref 1.14(0.94-1.39) 1.15(0.94-1.40) 1.50(1.24-1.83) Model 3 Ref 1.16(0.95-1.41) 1.16(0.95-1.42) 1.48(1.21-1.80) Model 4 Ref 1.13(0.93-1.38) 1.10(0.90-1.35) 1.34(1.09-1.64) * Quartiles defined on the entire study population Model 1: Adjusted for age, race, and sex Model 2: Adjusted for Model 1 + BMI and smoking Model 3: Adjusted for Model 2 + metabolic syndrome components (fasting hyperglycemia (BS&gt;100), hypertension (SBP&gt;130, DBP&gt;85 or anti-hypertension medications), hypertriglyceridemia (&gt;150 mg/dl), low HDL (&lt;40 mg/dl for men and &lt;50 mg/dl for women) and abdominal obesity (waist circumference &gt; 102 cm for men and &gt;88 cm for women))Model 4: Adjusted for Model 3 + diabetes mellitus

Pretransplantation Liver Function Impacts on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: A Study of 455 Patients

Liver dysfunction is frequent before allogeneic stem cell transplantation (allo-SCT). However, its characteristics and impact on transplantation outcomes are uncertain, especially in the reduced-intensity conditioning (RIC) setting. We analyzed 455 patients receiving an allo-SCT in 3 Spanish centers. Pretransplantation aspartate aminotransferase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), total bilirubin, and international normalized ratio were analyzed. Pretransplantation liver function test abnormalities were found in 94 (22%) patients. The most frequent cause of pretransplantation liver dysfunction was isolated elevation of GGT/AP (n = 49, 53%). Patients with high bilirubin levels before allo-SCT showed higher 4-year nonrelapse mortality (4y-NRM) (hazard ratio [HR] 2 [95% confidence interval [CI] 1.1-3.8] P = .02) and patients with high GGT levels showed higher 100-day NRM and lower 4-year overall survival (OS) (HR 3.4 [95% CI 1.8-6.7] P < .001, and HR 2 [95% CI 1.4-3], P = .001), respectively. High levels of transaminases did not influence on survival or mortality. In conclusion, hepatic dysfunction before allo-SCT is frequent and has an impact on transplantation outcomes. The best indicator of liver dysfunction still has to be determined.

Hepatic Toxicity After Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation: Incidence, Characteristics and Risk Factors In a Cohort of 452 Patients.

AbstractAbstract 3495 Introduction:Hepatic dysfunction is one of the most frequent and less studied complications in the setting of allogeneic stem cell transplantation (Allo). To analyze the incidence, characteristics, risk factors and impact on outcome of hepatic dysfunction in reduced intensity conditioning Allo (Allo-RIC) recipients we conducted a retrospective study in three large Spanish centers. Patients and Methods:We analyzed 452 consecutive patients receiving an Allo-RIC between February 1998 and December 2008. Median age was 53 years (range [rg] 18–71). The median follow-up for survivors was 4 years (rg 0.2–10) RIC consisted in fludarabine 150mg/m2 plus melfalan 70–140 mg/m2 or busulfan 8–10mg/kg. Grades of hepatic dysfunction were defined according to the National Cancer Institute criteria (3.0). Severe hepatic toxicity was considered in patients presenting grade III-IV abnormalities after Allo-RIC in at least one of the following: aspartate aminotransferase (AST), alanine aminotransaminase (ALT), gamma glutamyl transpeptidase (GGT), total bilirubin and protrombin time. Results:A total of 307 patients (68%) developed grade III-IV hepatic toxicity at a median time of 176 days (rg 0–3868) for a cumulative incidence of 69% (95%IC 63–76). A total of 123 (27%), 179 (40%), 140 (31%) and 132 (29%) patients developed grade III-IV levels of AST, ALT, GGT and bilirubin, respectively. Median time of detection of AST, ALT, GGT and bilirubin peaks in days was 177 (rg 0–1200), 168 (rg 0–2253), 452 (rg 257–3126) and 74 (rg 0–783), respectively. Grade III-IV protrombin time abnormalities were found in 23 (5%) patients at a median time of 69 days (11-3868). Main causes of severe hepatic toxicity after Allo were graft versus host disease (GVHD) (n=127, 41%) and pharmacological toxicity (n=32, 10%). In multivariate analysis, risk factors for the development of severe hepatic toxicity were unrelated donors (HR 1.4 [95%CI 1–1.9] p=0.03), use of busulfan in the conditioning regimen (HR 1.3 [95%CI 1–1.7] p=0.04) and high levels of bilirubin and GGT before transplant (HR 2.4 [95%CI 1.6–3.2] p<0.001 and HR 2.7 [95%CI 1.7–4.3] p<0.001, respectively). Patients with severe hepatic toxicity showed higher 4-years non-relapse mortality (NRM) (HR 1.5 [95%CI 1.1–2.1] =0.01) and lower 4-years overall survival (OS) (HR 1.7 [95%CI 1.2–2.5] =0.007). Regarding specific hepatic toxicities, patients with grade III-IV bilirubin levels showed higher NRM and lower OS (HR 3.4 [95%CI 2.3–5.2] p<0.001 and HR 2.5 [95%CI 1.7–3.8] p<0.001, respectively), while patients with grade III-IV protrombin time abnormalities had lower OS (HR 2 [95%CI 1.2–3.4], p=0.005). AST and ALT abnormalities after Allo did not have any impact on NRM and OS. Interestingly, patients with high GGT levels after Allo seemed to have a better outcome with lower NRM and higher OS (HR 0.1 [95%CI 0.1–0.2] p<0.001 and HR 0.2 [95%CI 0.1–0.4] p<0.001, respectively). Regarding GVHD, patients with severe hepatic toxicity did not show higher incidence of acute or chronic GVHD. Conclusion:Hepatic toxicity is frequent and diverse after Allo-RIC. Grade III-IV bilirubin levels were associated with worse outcome of the procedure while grades III-IV GGT levels seemed to be associated with better outcome. High transaminase levels did not show an impact in our patients. Disclosures:No relevant conflicts of interest to declare.

Low alpha‐fetoprotein hepatocellular carcinoma

A large proportion of hepatocellular carcinoma (HCC) patients do not secrete elevated levels of the tumor marker alpha-fetoprotein (AFP). There is little published guide to prognostic features of this patient subset. We interrogated a large HCC database in which all patients had been followed until death, to examine which features might be prognostically useful. We found 413 biopsy-proven unresectable HCC patients with low serum AFP values. Serum gamma glutamyl transpeptidase (GGTP) levels were one of the most significant factors for survival. This dichotomization into low and high GGTP levels separated the patients into distinctive survival ranges. Patients with GGTP levels < 110 U/100 mL and small tumors had longest survival > 795 days. Patients with GGTP > or = 110 U/mL and large tumors with the presence of portal vein thrombosis had the shortest survival range of 300-560 days. Serum levels of the onco-fetal protein GGTP represent a useful prognostic parameter in HCC patients with low AFP levels.

Clinical and virological effects of long‐term (over 5 years) lamivudine therapy

Ideally, long-term lamivudine therapy should not induce tyrosine-methionine-aspartate-aspartate (YMDD) mutants (reverse transcription [rt]; rt M204I/V) in patients with chronic hepatitis B. There is little or no information on the clinical features of patients who do not develop such mutants. We analyzed 368 patients who received lamivudine therapy for more than 6 months between 1995 and 2003. Among them, 98 patients were negative for YMDD mutants during 5-year lamivudine therapy. Multivariate analysis identified hepatitis B e antigen (HBeAg) negativity, lack of cirrhosis, and high gamma glutamyltranspeptidase (GGTP) level as independent factors associated with lack of emergence of YMDD mutants during 5-year treatment. In these 98 patients, 21 patients developed YMDD mutants in the 5-year posttreatment follow-up. Old age was identified as the only factor associated with the emergence of YMDD mutants during that period. For all patients, 53 showed no elevation of alanine aminotransferase (ALT) or viral load after emergence of YMDD mutants during 5 years. Short latency to emergence of YMDD mutants, mixed (tyrosine-isoleucine-aspartate-aspartate (YIDD) [rtM204I] + tyrosine-valine-aspartate-aspartate (YVDD) [rtM204V]) type, and low ALT level were identified as independent factors associated with elevation ALT or viral load. HBeAg negativity, lack of cirrhosis, and high GGTP level were associated with lack of emergence of YMDD mutants during 5-year period. Young age protected against emergence of YMDD mutants over the 5-year period. Moreover, after the emergence of YMDD mutants, short latency to the emergence of YMDD mutant, mixed type mutants, and low baseline ALT level were associated with elevation of ALT or viral load.