Elevated Γ-glutamyltransferase Research Articles

A phase I clinical trial investigating the safety, tolerability, and pharmacokinetics of HX301 (narazaciclib), a novel multi-kinase inhibitor targeting CSF1R, CDK 4/6, and ARK5, in patients with advanced solid tumors.

e15106 Background: HX301 (narazaciclib) is a promising novel multi-kinase inhibitor with potent activity against Colony Stimulating Factor 1 Receptor (CSF1R), Cyclin-Dependent Kinase 4/6 (CDK4/6), and Aurora Kinase 5 (ARK5), with a half-maximal inhibitory concentration (IC50) values in 0.29-4.95 nM range. It is an oral bioavailable agent and has the ability to cross blood-brain barrier. Preclinical data have showed significant antitumor activities, warranting further clinical trials to evaluate the safety, and potential efficacy in human subjects. Methods: Utilizing the standard 3+3 design, the study aimed to evaluate the safety, tolerability and pharmacokinetics of ascending doses of HX301. Patients with heavily pretreated advanced solid tumors received HX301single agent via oral administration, with doses ranging from 40mg to 200mg once daily for the first 21 days of each 28-day cycle. Results: As of December 27, 2023, a total of 20 patients (5 males, 15 females) were enrolled in the study, with varying doses of HX301 administered: 40 mg (n=3), 80 mg (n=3), 120 mg (n=4), 160 mg (n=3), and 200 mg (n=7). The median age of the patients was 55 years, ranging from 30 to 71. Notably, 15 patients (75%) had metastatic breast cancers. Dose-limiting toxicities (DLTs) were observed in 2 patients in the 200 mg group. These included a Grade 4 increase in alanine aminotransferase (ALT) and a Grade 3 decrease in platelet counts with associated epistaxis, both of which resolved after discontinuation of treatment. The most common treatment-related adverse events (AEs) observed were elevated aspartate aminotransferase (AST) (65.0%), decreased white blood cell count (50%), decreased neutrophil count (50%), elevated ALT (45%), elevated creatine kinase (45%), and elevated creatinine (35%). Additionally, 4 patients experienced Grade 3 or higher treatment-related AEs, including 1 patient in the 160 mg group with Grade 3 elevated γ-glutamyl transferase and alkaline phosphatase, and 3 patients in the 200 mg group with Grade 4 elevated ALT and Grade 3 elevated AST and Dyspepsia, Grade 3 decreased neutrophil and platelet counts, and Grade 3 hyperglycemia. Notably, no AEs led to death. Among the 20 patients evaluable for tumor assessment using RECIST 1.1 by Investigators, 4 obtained stable disease, including 2 patients in the 200 mg group, 1 in the 120 mg group, and 1 in the 80 mg group. Furthermore, 1 patient with HR+ breast cancer in the 200 mg group received study drug for over a year and achieved prolonged stable disease for more than 12 months, highlighting a notable clinical outcome. Conclusions: HX301 at dose levels ranging from 40mg to 160mg was tolerable with a manageable toxicity profile. Further clinical studies are needed to explore the drug's anti-tumor activity, particularly in combination settings. Clinical trial information: NCT05731934 .

Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial

Adrenocortical carcinoma is a rare malignancy with poor response to systemic chemotherapy. Mitotane is the only approved therapy for adrenocortical carcinoma. Cabozantinib is a multikinase inhibitor approved in multiple malignancies. This is the first prospective trial to explore the anti-tumour activity, safety, and pharmacokinetic profile of cabozantinib in patients with advanced adrenocortical carcinoma. This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with advanced adrenocortical carcinoma was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible patients had histologically confirmed adrenocortical carcinoma, were not candidates for surgery with curative intent, had measurable disease, had an estimated life expectancy of at least 3 months, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 with adequate organ function. Patients who had used mitotane within 6 months of study participation were required to have a serum mitotane level of less than 2 mg/L. Patients were given oral cabozantinib 60 mg daily with the option of dose reduction to manage adverse events. The primary endpoint was progression-free survival at 4 months, assessed in all patients who received at least one dose of study drug per protocol. This study is registered with ClinicalTrials.gov, NCT03370718, and is now complete. Between March 1, 2018, and May 31, 2021, we enrolled 18 patients (ten males and eight females), all of whom received at least one dose of study treatment. Of the 18 patients, eight (44%) had an ECOG performance status of 0, nine (50%) patients had a performance status of 1, and one (6%) patient had a performance status of 2. Median follow-up was 36·8 months (IQR 30·2-50·3). At 4 months, 13 (72·2%; 95% CI 46·5-90·3) of 18 patients had progression-free survival and median progression-free survival was 6 months (95% CI 4·3 to not reached). One patient remains on treatment. Treatment-related adverse events of grade 3 or worse occurred in 11 (61%) of 18 patients. The most common grade 3 adverse events were lipase elevation (three [17%] of 18 patients), elevated γ-glutamyl transferase concentrations (two [11%] patients), elevated alanine aminotransferase concentrations (two [11%] patients), hypophosphatemia (two [11%] patients), and hypertension (two [11%] patients). One (6%) of 18 patients had grade 4 hypertension. No treatment related deaths occurred on study. Cabozantinib in advanced adrenocortical carcinoma showed promising efficacy with a manageable and anticipated safety profile. Further prospective studies with cabozantinib alone and in combination with immune checkpoint therapy are ongoing. Exelixis.

Chidamide Combined with a Modified Bu-Cy Conditioning Regimen Improves Survival in Patients with T-Cell Acute Lymphoblastic Leukemia/Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Backgrounds: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL). Relapse post-HSCT remains the major cause of mortality, highlighting the urgent need for more effective conditioning regimens in reducing relapse rates and improving outcomes for T-cell malignancy. Chidamide, as the first oral subtype-selective histone deacetylase inhibitor (HDACi) approved in China, can lead to a more relaxed chromatin structure through chromatin remodeling, particularly hyperacetylation of lysine residues in the histone tails, which facilitates the expression of tumor suppressor genes as well as the action of alkylating agents busulfan. To date, the role of chidamide in T-ALL/LBL conditioning regimens in allo-HSCT has not been explored. Methods: We retrospectively compared the clinical efficacy and safety between chidamide combined with a modified Busulfan-Cyclophosphamide (mBuCy) and mBuCy conditioning regimen for T-ALL/LBL patients undergoing allo-HSCT. The chidamide combined with mBuCy regimen was presented in Figure1. Results: Twenty-two patients received chidamide combined with mBuCy conditioning regimen (Chi group). A matched-pair control (CON) group of 44 patients (matched 1:2) received mBuCy only. The median follow-up time was 683 (range 296-1168) days. Patients in the Chi group showed better 2-year overall survival (OS) and leukemia-free survival (LFS) (85.4 vs. 52.9%, respectively, P = 0.021; 69.1 vs. 42.9%, respectively, P = 0.031). Multivariate analysis showed that chidamide combined with mBuCy was a major positive risk factor for OS (HR 0.18, 95%CI, 0.05-0.63; P = 0.007) and LFS (HR 0.32; 95%CI, 0.13-0.80; P = 0.015). The cumulative incidence rates of grade II-IV and grade III-IV aGVHD were similar (36.4 vs. 38.6%, respectively, P = 0.858; 13.6 vs. 20.5%, respectively, P = 0.735). Patients in the Chi group showed higher incidence of elevated γ-glutamyltransferase and hemorrhagic cystitis than that in the mBuCy group (90.9 vs. 65.9%, respectively, P = 0.029; 36.4 vs. 13.6%, respectively, P = 0.007). No transplantation-related mortality was documented within the first 100 days after transplantation. Conclusions: Our data demonstrate that the conditioning regimen containing chidamide improves the survival of T-ALL/LBL patients without increasing the incidence of transplant-related mortality. A prospective clinical trial is expected to confirm these findings.

Long-Term Cumulative Exposure to High γ-Glutamyl Transferase Levels and the Risk of Cardiovascular Disease: A Nationwide Population-Based Cohort Study.

Elevated γ-glutamyl transferase (γ-GTP) levels are associated with metabolic syndrome. We investigated the association of cumulative exposure to high γ-GTP with the risk of cardiovascular disease (CVD) in a large-scale population. Using nationally representative data from the Korean National Health Insurance system, 1,640,127 people with 4 years of consecutive γ-GTP measurements from 2009 to 2012 were included and followed up until the end of 2019. For each year of the study period, participants were grouped by the number of exposures to the highest γ-GTP quartile (0-4), and the sum of quartiles (0-12) was defined as cumulative γ-GTP exposure. The hazard ratio for CVD was evaluated using the Cox proportional hazards model. During the 6.4 years of follow-up, there were 15,980 cases (0.97%) of myocardial infarction (MI), 14,563 (0.89%) of stroke, 29,717 (1.81%) of CVD, and 25,916 (1.58%) of death. Persistent exposure to high γ-GTP levels was associated with higher risks of MI, stroke, CVD, and death than those without such exposure. The risks of MI, stroke, CVD, and mortality increased in a dose-dependent manner according to total cumulative γ-GTP (all P for trend <0.0001). Subjects younger than 65 years, with a body mass index <25 kg/m2, and without hypertension or fatty liver showed a stronger relationship between cumulative γ-GTP and the incidence of MI, CVD, and death. Cumulative γ-GTP elevation is associated with CVD. γ-GTP could be more widely used as an early marker of CVD risk, especially in individuals without traditional CVD risk factors.

Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients.

Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed. Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2. Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ-glutamyltransferase (GGT) (p=.041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p=.038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in-silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p=.003). Comparing this to patients with likely benign (LB) variants, the patients with likely-pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p=.0001). Significantly more patients with LP variants had extra-hepatic phenotypes of ALGS compared with those patients with LB variants (p=.0004). When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in-silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.

Heterotopic pancreas in the liver: a rare cause of recurrent attacks of cholangitis mimicking Caroli’s disease

A 41-year-old man with a history of gallstone disease, who had undergone ERCP and cholecystectomy 3 months earlier, presented in our department with recurrent episodes of abdominal pain and fever. Biochemistry showed only slightly elevated γ-glutamyltransferase (185 U/L), and his inflammation markers were markedly above the normal range.

Insights into the ecotoxicological perturbations induced by the biocide Abamectin in the white snail, Theba pisana

Abamectin (avermectin B1, ABM) has been widely used as a biocide in agriculture, veterinary and medicine around the world. Yet, there is still a lack of knowledge about the ecotoxicological effects of ABM. In this study, we investigated the acute toxicity and sub-lethal (20% and 60% LD50) biochemical responses of ABM on the non-target land snail, Theba pisana. Mortality of snails increased with the dose increase, resulting 48 h- LD50 value of 1.048 µg/snail. The biochemical results showed a decrease in glycogen content and lipids for two sub-lethal doses after all time intervals, whereas increased the level of total proteins after exposure to 60% LD50 ABM. Overall, the tested sub-lethal doses significantly decreased the total energy reserves. ABM-exposure to snails elevated γ-Glutamyl transferase and Lactate dehydrogenase activities at all-time intervals. A significant increase of Glutathione-S-transferase activity was also recorded in snails exposed to 20% and 60% LD50 after 7 days and all time intervals, respectively. However, ABM inhibited the activity of Aspartate aminotransferase and Alanine aminotransferase after 7 days of exposure. Our investigation provides new insights into the disturbances of energy reserves and enzyme activities in T. pisana that are sensitive and may be used as biomarkers for assessing ABM toxicity.

Unusual Presentation of Epstein-Barr Virus-Associated Cholestatic Hepatitis in an Infant

Epstein-Barr virus (EBV) infections are prevalent in the pediatric population but are subclinical in the majority of cases. Elevated transaminases in the acute setting rarely increase beyond 5 times the normal upper limit. We present a girl aged 1 y with fever, vomiting, and diarrhea. Although initial physical examination was unremarkable, she developed jaundice, hepatomegaly, abdominal distension, and a maculopapular rash during admission. Laboratory investigations revealed marked increase in transaminases (alanine aminotransferase 7,664.5 IU/L, aspartate aminotransferase 12,266 IU/L), elevated γ-glutamyl transferase (224 IU/L), and hyperbilirubinemia (total 130.7 µmol/L, direct 104.9 µmol/L). Abdominal ultrasound reported hepatomegaly with mild ascites. Serology revealed that both Monospot test and EBV immunoglobulin G were positive. With supportive therapy, improvement was noted within a week of symptom onset. We hereby elucidate the importance of considering EBV as a cause of acute cholestatic hepatitis in a very young pediatric patient who develops a rapid elevation of liver enzymes.

Repeatedly elevated γ-glutamyltransferase levels are associated with an increased incidence of digestive cancers: A population-based cohort study.

BACKGROUNDThe association between elevated γ-glutamyltransferase (GGT) at a certain point and incident cancer has been suggested; however, no study has evaluated the association between repeatedly elevated GGT and cancer incidence. AIMTo investigate the effects of repeatedly elevated GGT on the incidence of digestive cancers.METHODSParticipants who had undergone health screening from 2009 to 2012 and 4 consecutive previous examinations were enrolled. GGT points were calculated as the number of times participants met the criteria of quartile 4 of GGT in four serial measurements (0-4 points). Multivariable Cox proportional hazard regression models were applied. RESULTSIn total, 3559109 participants were included; among them, 43574 digestive cancers developed during a median of 6.8 years of follow-up. The incidence of total digestive cancers increased in a dose-response manner in men [adjusted hazard ratio (aHR) compared with those with 0 GGT points = 1.28 and 95% confidence interval (CI) = 1.24-1.33 in those with 1 point; aHR = 1.40 and 95%CI = 1.35-1.46 in those with 2 points; aHR = 1.52 and 95%CI = 1.46-1.58 in those with 3 points; aHR = 1.88 and 95%CI = 1.83-1.94 in those with 4 points; P for trend < 0.001]. This trend was more prominent in men than in women and those with healthy habits (no smoking, no alcohol consumption, and a low body mass index) than in those with unhealthy habits.CONCLUSIONRepeatedly elevated GGT levels were associated with an increased risk of incident digestive cancer in a dose-responsive manner, particularly in men and those with healthy habits. Repeated GGT measurements may be a good biomarker of incident digestive cancer and could help physicians identify high-risk populations.

Liver function changes following the introduction of a gluten-free diet in patients with celiac disease.

Aim of the studyDisturbance in liver enzymes is a well-described observation in patients with celiac disease (CD). We aim to describe the prevalence of all liver function abnormalities in CD and assess their response to a gluten-free diet (GFD).Material and methodsThis is a retrospective cross-sectional study of all CD patients diagnosed from 2007 to 2020 in King Abdulaziz University Hospital, Jeddah. Demographic, biochemical, and histologic patient data were collected.ResultsThe study included 132 patients with CD. The median age was 9.5 years (range, 1-18 years). Males constituted 56.1% (n = 74) of the whole cohort. The most common associated morbidities were type 1 diabetes (33%), thyroid disease (15.7%), and Down syndrome (7.6%). Ninety-seven percent of patients were determined to have a severe form of CD (Marsh score 3). Aspartate aminotransferase (AST) was high in 38 patients (28.8%), while alanine aminotransferase (ALT) was high in 10 (7.6%). Two patients (1.5%) had elevated γ-glutamyl transferase (GGT) levels, and 2 patients (1.5%) had elevated AST, ALT, and GGT levels. Albumin levels were low in 29 patients (22%), while bilirubin levels were elevated in 1 patient. Introduction of a GFD resulted in improvement in ALT levels at 6 months, and improvement in albumin levels both after 6 months and 12 months.ConclusionsTransaminase and albumin disturbances are frequently found in CD, with the most common abnormality being elevated AST. A decreased ALT level is the most pronounced response to a GFD.

Impact of Liver Test Abnormalities and Chronic Liver Disease on the Clinical Outcomes of Patients Hospitalized with COVID-19

Background and Aims: The impact of SARS-CoV-2 infection on the liver and the possibility of chronic liver disease (CLD) as a risk factor for COVID-19 severity is not fully understood. Our goal was to describe clinical outcomes of COVID-19 inpatients regarding the presence of abnormal liver tests and CLD. Methods: A retrospective analysis of patients with SARS-CoV-2 infection, hospitalized in a tertiary center in Portugal, was performed. Studied outcomes were disease and hospitalization length, COVID-19 severity, admission to intensive care unit (ICU) and mortality, analyzed by the presence of abnormal liver tests and CLD. Results: We included 317 inpatients with a mean age of 70.4 years, 50.5% males. COVID-19 severity was moderate to severe in 57.4% and critical in 12.9%. The mean disease length was 37.8 days, the median hospitalization duration 10.0 days and overall mortality 22.8%. At admission, 50.3% showed abnormal liver tests, and 41.5% showed elevated aminotransferase levels, from which 75.4% were mild. Elevated aminotransferase levels at admission were associated with COVID-19 severity (78.7 vs. 63.3%, p = 0.01), ICU admission (13.1 vs. 5.92%, p = 0.034) and increased mortality (25.8 vs. 13.3%, p = 0.007). However, in a subgroup analysis, only aspartate transaminase (AST) was associated with these worse outcomes. Alkaline phosphatase was elevated in 11.4% of the patients and was associated with critical COVID-19 (21.1 vs. 9.92%, p = 0.044) and mortality (20.4 vs. 9.52%, p = 0.025), while 24.6% of the patients showed elevated γ-glutamyl transferase, which was associated with ICU admission (42.3 vs. 22.8%, p = 0.028). Fourteen patients had baseline CLD (4.42%), 3 with liver cirrhosis. Alcohol (n = 6) and nonalcoholic fatty liver disease (n = 6) were the most frequent etiologies. CLD patients had critical COVID-19 in 21.4% (p = 0.237), mean disease length of 36.6 days (p = 0.291), median hospitalization duration of 11.5 days (p = 0.447) and a mortality rate of 28.6% (p = 0.595), which increased to 66.7% among cirrhotic patients (p = 0.176). Conclusions: Liver test abnormalities in COVID-19 patients were frequent but most commonly mild. AST, but not alanine transaminase, was associated with worse clinical outcomes, such as COVID-19 severity and mortality, probably indicating these outcomes were independent of liver injury. A low prevalence of CLD was seen, and a clear impact on COVID-19 outcomes was not seen.

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy

Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks). A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. ClinicalTrials.gov Identifier: NCT03375164.

Thyroid Function in Patients With a Fontan Circulation

In this study, we tested our hypothesis that thyroid function is impaired and contributes to perturbed hemodynamics in patients after Fontan operation. Cardiac catheterization and blood tests for thyroid function were performed in 37 patients who underwent a Fontan operation. Among them, 12 patients (33%) had subclinical thyroid dysfunction with an elevated thyroid-stimulating hormone level despite normal thyroxine levels. Thyroid-stimulating hormone levels were significantly correlated with central venous pressure (p <0.01, R2 = 0.3), and patients with subclinical hypothyroidism showed significantly elevated γ-glutamyltransferase level, an indicator of liver congestion, compared with the other patients (125.6 ± 12.2 vs 67.6 ± 4.6 IU/L, p <0.01). In addition, the levels of free triiodothyronine, an effective thyroid hormone, were significantly lower in patients with subclinical hypothyroidism than in those with normal thyroid function (3.1 ± 0.1 vs 3.5 ± 0.1 pg/dl, p <0.01). The free triiodothyronine level was significantly and negatively correlated with the relaxation time constant (p = 0.03) and brain natriuretic hormone (p <0.01) level and positively correlated with the cardiac index (p = 0.04). In conclusion, venous congestion in Fontan patients may cause thyroid dysfunction, which can be responsible for decreased ventricular function and cardiac output in Fontan patients. Thus, thyroid function should be routinely monitored after Fontan surgery.

Long-term risk for end-stage kidney disease and death in a large population-based cohort

Knowledge of metabolic risk factors for end-stage kidney disease (ESKD) in the general population is limited when considering the competing event death in risk analysis. The aim of our prospective observational study was to investigate how blood pressure and metabolic factors might influence the risks for ESKD and death before ESKD in a large Austrian population-based cohort with long-term follow-up. 177,255 participants (53.8% women; mean age 42.5 years) were recruited between 1988 and 2005 and linked to the Austrian Dialysis and Transplant Registry and the National Mortality Registry. Over a mean follow-up of 16 years 358 participants reached ESKD and 19,512 participants died. Applying fully adjusted cause-specific Cox proportional hazards models elevated fasting blood glucose, hypertension, hypertrigylceridemia and hypercholesterolemia were associated with a higher relative risk for ESKD than for death before ESKD, whereas elevated γ-glutamyltransferase was associated with an increased relative risk of death but not ESKD. Results were similar using continuous or categorical exposure variable measures in the general cohort but differed in selected high-risk populations. These findings might help improve the design of renal risk factor modification trials and kidney disease awareness and prevention programs in the general population, which may ultimately decrease the burden of ESKD.

Low Serum Lysosomal Acid Lipase Activity Correlates with Advanced Liver Disease

Fatty liver has become the most common liver disorder and is recognized as a major health burden in the Western world. The causes for disease progression are not fully elucidated but lysosomal impairment is suggested. Here we evaluate a possible role for lysosomal acid lipase (LAL) activity in liver disease. To study LAL levels in patients with microvesicular, idiopathic cirrhosis and nonalcoholic fatty liver disease (NAFLD). Medical records of patients with microvesicular steatosis, cryptogenic cirrhosis and NAFLD, diagnosed on the basis of liver biopsies, were included in the study. Measured serum LAL activity was correlated to clinical, laboratory, imaging and pathological data. No patient exhibited LAL activity compatible with genetic LAL deficiency. However, serum LAL activity inversely predicted liver disease severity. A LAL level of 0.5 was the most sensitive for detecting both histologic and noninvasive markers for disease severity, including lower white blood cell count and calcium, and elevated γ-glutamyltransferase, creatinine, glucose, glycated hemoglobin, uric acid and coagulation function. Serum LAL activity <0.5 indicates severe liver injury in patients with fatty liver and cirrhosis. Further studies should define the direct role of LAL in liver disease severity and consider the possibility of replacement therapy.

Acitretin-induced hepatitis: when to monitor cholestatic enzymes.

Acitretin is a systemic retinoid that is used in dermatology for a variety of conditions. A well-recognized potential adverse event from acitretin is elevated transaminases, indicating acute hepatocyte damage. Less well known is the possible cholestatic injury that can occur, signaled by elevated γ-glutamyltransferase (GGT) and alkaline phosphatase (ALP). Our patient presented with an acute acitretin-induced hepatitis with a mixed pattern of elevated transaminases as well as GGT and ALP. A literature review demonstrated that most cases of acitretin-induced hepatitis, outside clinical trials, describe patients with a similar mixed hepatitis pattern. This is the first literature review on acitretin-induced hepatitis. Although acitretin-induced hepatoxicity is rare, the seemingly unusual presentation of a mixed pattern of hepatocyte injury and cholestasis may be more common than previously thought. The findings should encourage clinicians not only to monitor transaminases but also to consider measuring cholestatic enzymes (ALP/GGT) in patients with transaminase abnormalities.

Relationship between serum γ-glutamyltransferase level and leukocyte count in Korean children and adolescents

Background. Elevated γ-glutamyltransferase (GGT) is an important risk factor for cardiometabolic diseases, which may result from chronic low-grade inflammation. Leukocyte count is widely considered a marker of inflammation and is also an independent predictor of cardiometabolic diseases. This study aimed to determine the relationship between GGT and leukocyte count in a representative sample of Korean children and adolescents. Methods. A nationwide cross-sectional study was conducted to examine the relationship between GGT and leukocyte count in 830 boys and 714 girls (aged 10–18 years), using data from the 2010–2012 Korean National Health and Nutrition Examination Survey. The odds ratios (ORs) and 95% confidence intervals (CIs) for high leukocyte count (≥ 75th percentile) were calculated across GGT quartiles using multiple logistic regression analyses. Results. Leukocyte count gradually increased in accordance with serum GGT quartiles in both boys and girls (all p-values < 0.001). The OR (95% CI) for high leukocyte of the highest GGT quartile was 2.19 (1.05–4.58) for boys and 2.36 (1.13–4.93) for girls after adjusting for age, BMI, blood pressure, total cholesterol, triglyceride, physical activity, household income, and residential area. Similarly, these positive associations were observed in multiple logistic regression analysis using log2-transformed serum GGT as a continuous variable. Conclusions. The present study demonstrates a positive relationship between serum GGT and leukocyte count. These findings indicate that serum GGT may be closely related with subclinical low-grade inflammation in children and adolescents.

Revisiting predictors of virologic response to PEGIFN + RBV therapy in HIV-/HCV-coinfected patients: the role of metabolic factors and elevated GGT levels

Evaluation of metabolic factors and elevated γ-glutamyltransferase (GGT) levels as independent predictors of treatment failure in a thoroughly documented cohort of HIV-/HCV-coinfected patients (HIV/HCV). Sixty-four HIV/HCV patients treated with pegylated interferon-α-2a plus ribavirin (PEGIFN+RBV) at the Medical University of Vienna within a prospective trial were included in this study. In addition, 124 patients with HIV/HCV from the AIFA-HIV and AHIVCOS cohorts were included as a validation cohort. Advanced liver fibrosis, GGT elevation, insulin resistance (IR) and low CD4+nadir were defined as METAVIR F3/F4, GGT levels >1.5× sex-specific upper limit of normal, homoeostasis model assessment of insulin resistance >2 and CD4+nadir <350cells/μL, respectively. HCV-genotype 1/4 (OR26.3; P=0.006), advanced liver fibrosis (OR20.2; P=0.009), interleukin 28B rs12979860 non-C/C SNP (OR8.27; P=0.02) and GGT elevation (OR7.97; P=0.012) were independent predictors of treatment failure, while both IR (OR3.51; P=0.106) and low CD4+nadir (OR2.64; P=0.263) were not independently associated with treatment failure. A statistically significant correlation between GGT elevation and prior alcohol abuse (r=0.259; P=0.039), liver steatosis (r=0.301; P=0.034) and low-density lipoprotein-cholesterol (r=-0.256; P=0.041) was observed. The importance of GGT elevation as an independent predictor of treatment failure was confirmed in a validation cohort (OR2.76; P=0.026). While GGT elevation emerged as an independent predictor of treatment failure in both the derivation and the validation cohort, no independent associations between metabolic factors and treatment failure were observed. Thus, our findings suggest that GGT elevation is an independent predictor of treatment failure in HIV/HCV that can easily be incorporated into predictive algorithms.

Late Consequences of Traumatic Rupture of the Diaphragm

A 54-year-old man was admitted to our clinic due to elevated γ-glutamyltransferase, without any clinical symptoms. About 25 years ago, he had undergone blunt abdominal and thoracic trauma during an accident. No diagnostic measures or therapy had been performed at that time. Serum bilirubin was normal, but the values for alanine transaminase, aspartate transaminase, and alkaline phosphatase were slightly above the reference range. Sonography of the abdomen revealed dilated intrahepatic bile ducts up to 3 mm in diameter and steatosis of the liver grade I. CT scan and MRI of the thorax and abdomen showed a giant hiatal hernia with transposition of upper abdominal organs into the chest. As the patient presented clinically completely asymptomatic, without dyspnea, dysfunction of phonation or ingestion, we decided a conservative treatment with Ursodesoxycholic acid. The liver values resolved with this regimen gradually. At follow-up examination 1 year later, they had normalized. Spirometry showed a reduced lung capacity (3.44 L; 64.4% of the desired value) and a reduced FEV1 (forced expiratory volume in one second) of 2.84 L (70.2% of the desired value). Further diagnostics revealed normal otorhinolaryngological and phoniatric findings including stroboscopy of the vocal folds and voice range profile.

1125P - Open-Label Pilot Study of Vemurafenib in Previously Treated Metastatic Melanoma (MM) Patients (PTS) with Symptomatic Brain Metastases (BM)

ABSTRACT Background The BRAF inhibitor vemurafenib has shown high response rates and improved progression-free and overall survival in mM harbouring V600-mutated BRAF. BMs are often observed with mM and indicate a poor prognosis. The aim of this preliminary investigation is to determine the feasibility of vemurafenib therapy in mM with BM. Methods 24 evaluable pts with BRAFV600 mutation positive (cobas® 4800 BRAF V600 Mutation Test) mM and BMs, requiring corticosteroids for symptom control, were enrolled (Nov 2010–Nov 2011). Pts received twice-daily vemurafenib 960 mg. Primary endpoint is safety; secondary endpoint is best overall response rate (RECIST v1.1). Results All pts were white, median age 47 (24–70) years. Median baseline number of BMs was 3.5 (1–20). Median time since BM diagnosis was 3.2 (0–64) months. Other lesion sites included skin, lung, liver, bone, lymph nodes, colon/large intestine, stomach, breast and adrenal. All pts had prior treatment for BM: radiotherapy 83% (58% whole brain, 25% precision), 2 pts had surgery and 83% of pts had systemic therapy. As of clinical data cut-off (15 Dec 2011), median treatment duration was 117 (3–304) days. 9 pts are ongoing; 15 (63%) discontinued treatment because of progression of disease (PD), 8 of whom died because of PD. 22 pts (92%) reported ≥1 adverse event (AE), which were mainly mild or moderate. Most common AEs were arthralgia (33%), photosensitivity (21%) and seizures (20%, pre-existing). 3 pts reported 1 of each of the following grade 3 AEs: epilepsy, cutaneous squamous cell carcinoma (cuSCC), increased amylase, elevated γ-glutamyltransferase and ileus with perforation. Overall, cuSCC occurred in 3 pts (12.5%), skin papilloma in 3 pts (12.5%) and keratoacanthoma in 1 pt (4.2%). 7/24 pts (29%) had a confirmed partial response: 9 pts (38%) had stable disease, 3 (12%) PD and 5 (21%) were not evaluable for response. Median duration of response was 3.8 (0.8–4.7) months. Conclusions Vemurafenib therapy is feasible in advanced melanoma patients with symptomatic BM. Interpretation of efficacy is currently limited because of a short follow-up time, but there are strong indications of vemurafenib activity in BM. Disclosure R. Dummer: Research funding: Astra Zeneca, Novartis, Cephalon, MSD, Transgene, BMS, Roche, GlaxoSmithKline, Bayer. Ad-board: Astra Zeneca, Novartis, Cephalon, MSD, Transgene, Genta, Bayer, Roche, BMS, GSK, Spirig. L. Mitchell: Full-time employee of F. Hoffmann-la-Roche. L. Veronese: Full time employee at F. Hoffmann-la-Roche. All other authors have declared no conflicts of interest.