Increased Gamma-glutamyl Transpeptidase Research Articles

Are Selected Cytokines and Epstein-Barr Virus DNA Load Predictors of Hepatological Complications of Epstein-Barr Virus Infection in Children?

The aim of the study was to evaluate tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6), soluble intracellular adhesion molecules 1 (s-ICAM-1) and Epstein-Barr virus (EBV) DNA load levels as predictors of hepatological complications of EBV infection in children. The study group consisted of 54 children aged one to eighteen years, who were hospitalised from 1 December 2018 to 31 December 2020 in the Department of Paediatrics, Infectious Diseases and Hepatology and who had hepatological complications in the course of serologically and molecularly confirmed EBV infection. It was shown that IL-6, TNF-α, and s-ICAM-1 concentrations were the highest in patients with hepatitis and biliary pole damage. Higher EBV DNA viremia positively correlated with increased C-reactive protein (CRP) and TNF-α levels and increased leukocyte, lymphocyte, and monocyte counts. Increases in lymphocyte counts and TNF-α concentrations were observed along with increases in gamma-glutamyl transpeptidase (GGTP) activity. Increased concentrations of IL-6, TNF-α, and s-ICAM-1 may indicate the risk of hepatitis with concomitant biliary pole damage during EBV infection.

Associations of polycyclic aromatic hydrocarbons, water-soluble ions and metals in PM2.5 with liver function: Evidence from schizophrenia cohort

BackgroundFine particulate matter (PM2.5) was reported to impact liver function, but the roles of specific PM2.5 chemical components remained to be explored. Besides, severe liver dysfunction in schizophrenia patients deserves attention. ObjectiveTo investigate the associations of short-term PM2.5 components with liver function in schizophrenia patients. MethodsA repeated-measures study based on schizophrenia cohort including 1023 visits (n = 446) was conducted during 2017–2020. Liver function was reflected by 10 indicators including liver enzymes, proteins and bilirubin et al. Monitoring data of PM2.5 and its components, including 16 polycyclic aromatic hydrocarbons (PAHs), 4 water-soluble ions and 10 metals were collected. Linear mixed effect and Bayesian kernel machine regression (BKMR) models were used to evaluate the single and combined effects of PM2.5 components (0–3 day) on liver function in schizophrenia patients. ResultsSeveral PAHs were significantly associated with liver enzymes, while water-soluble ions and metal components had almost no association. Specifically, with per interquartile range (IQR) increased in Fluoranthene, levels of alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transpeptidase (GGT) increased by 2.06 %, 5.07 %, 4.94 % and 5.56 %, respectively. An IQR increases in Benzo[a]pyrene was significantly associated with 6.62 %, 3.67 % and 7.83 % increase in ALT, AST and GGT. Almost all PAHs, sulfate, nitrate, ammonium, Sb, Al, As, Pb, Mn and Tl were positively associated with albumin (ALB). Phenanthrene was associated with increased levels of direct bilirubin (DBIL) and total bilirubin (TBIL). The combined effects of significant PM2.5 components on ALP, GGT, ALB, globulin (GLOB), ratio of albumin to globulin (A/G), TBIL and total bile acid (TBA) were found by BKMR, respectively. ConclusionsFindings highlight the short-term combined effects of PM2.5 components, especially PAHs, on liver function in schizophrenia patients, which contribute to the management of PM2.5 sources including combustion activities and traffic emissions as well as improving schizophrenia comorbidities.

Microbiota and Serum Metabolic Profile Changes in Korean Native Hanwoo Steer in Response to Diet Feeding Systems.

The diversity of bacteria and their function in cattle gastrointestinal tracts can influence animal welfare. Next-generation sequencing (NGS) was used to investigate microbial diversity in the feces of Hanwoo steers reared under natural grazing (GS) and housing (HS) systems. Additionally, serum metabolic parameters, such as liver and kidney markers and mineral and lipid content changes, as well as their correlation with pyrotags, were studied. A total of 6468 ± 87.86 operational taxonomic units (OTUs) were identified in both steer groups, of which 3538 ± 38.17 OTUs were from grazing steer and 2930 ± 94.06 OTUs were from GS. Chao1 index analysis revealed a higher bacterial richness in GS. The dominant bacterial taxa were Bacteroidetes and Firmicutes. GS showed lower Bacteroidetes and higher Firmicutes abundance than HS. The serum of HS showed consistent increases in gamma-glutamyl transpeptidase (γGTP), glucose (GLU), total cholesterol (T-CHO), and triglyceride (TG) levels. The impact of GS on animal health and serum metabolic markers was strongly correlated with microbiota. As shown in this study, grazing has a significant impact on the fecal microbiota at the phylum and family levels, as well as the serum biochemical metabolites of Hanwoo steers.

Anti-parasitic effects of resveratrol on protoscolices and hydatid cyst layers

The main goal of the current study was to evaluate the effectiveness of resveratrol (RESV) on protoscolices and hydatid cysts of Echinococcus granolosus. Echinococcus granolosus protoscolices and hydatid cyst were exposed to RPMI, DMSO, formalin, mebendazole, and different concentrations of RESV in vitro. Then, viability, GGT, and caspase-3 activity of protoscolices were evaluated using light microscopy, colorimetric, and enzymatic assay, respectively. Tissue changes and expression of caspase-3 apoptosis were analyzed on the hydatid cyst wall by histologic and immunohistochemistry methods. The cell toxicity effect of RESV was evaluated on mouse PBMCs by Annexin V-FITC assay. The RESV-treated protoscolices showed loss of viability, increased gamma-glutamyl transpeptidase, and caspase-3 activity with significant differences compared to all control groups (P < 0.05). Dose and time dependence of mortality, GGT, and caspase-3 enzymatic activity was confirmed in the protoscolices of Echinococcus granulosus treated by RESV. Also, the tissue changes and apoptosis were prominent in RESV-treated hydatid cyst layers; however, tissue changes were only time-dependent, and RESV concentration had no apparent effect on tissue. In cell toxicity evaluation, RESV is safe without any significant apoptosis induction from 31.5 to 250 μg/ml; however, it was significant at 350 and 500 μg/ml in PBMCs.

Ураження печінки у хворих на неспецифічний виразковий коліт

Актуальність. Стаття присвячена темі хронічних запальних захворювань кишечника, зокрема, приділяється увага неспецифічному виразковому коліту (НВК). НВК перебігає з розвитком низки позакишкових уражень, серед яких особливе місце відводиться змінам печінки і жовчовивідних шляхів. У зв’язку з цим було проведено дослідження, метою якого була оцінка поширеності, характеру і клінічних особливостей уражень печінки у хворих на НВК. Матеріали та методи. Під наглядом перебувало 180 пацієнтів із НВК, підтвердженим ендоскопічно і морфологічно. Усім пацієнтам проводили мультимодальне ультразвукове дослідження печінки, досліджували біохімічні ознаки цитолізу і/або холестазу при негативних серологічних маркерах вірусного гепатиту В, С, D і аутоімунного гепатиту. Також проводили біохімічне дослідження ліпідного спектра крові, а пацієнтам із підозрою на аутоімунні ураження печінки — аналіз спектру відповідних антитіл. Результати. Зі 180 хворих на НВК ураження печінки виявлені у 58 (32,2 %). Паренхіматозні ураження печінки виявлені у 40 (22,2 %) хворих на НВК, а зміни з боку жовчовивідних шляхів — у 18 (10,0 %) пацієнтів із НВК. Неалкогольний стеатогепатит (НАСГ), аутоімунний гепатит (АГ) і первинний біліарний цироз (ПБЦ) печінки виявлені у 40 (69,0 %) пацієнтів з НВК, а ураження поза- і жовчних проток і жовчного міхура — у 18 (31,0 %). Серед паренхіматозних уражень печінки домінував НАСГ (53,5 %). АГ діагностовано у 8,6 % пацієнтів, ПБЦ — у 5,2 % хворих на НВК. Усі хворі на НВК з НАСГ крім базисної терапії приймали препарат есенціальних фосфоліпідіву добовій дозі 1800 мг (по 2 капсули 3 рази на день) протягом трьох місяців. Після закінчення лікування тільки у 2 (6,5 %) пацієнтів зберігалися незначні скарги. До лікування у всіх обстежених хворих було виявлене достовірне підвищення АСТ і АЛТ в 2,3 і 2,2 раза відповідно, у поєднанні з підвищенням ГГТ в 3,7 раза порівняно з нормою, що може свідчити про помірно виражений синдром цитолізу. Після лікування у хворих відзначена тенденція до нормалізації ферментативного статусу, хоча показники залишалися підвищеними порівняно з нормою. Висновки. Ураження печінки виявлені у 32,2 % хворих, переважно при поширених формах, середньотяжкому і тяжкому перебігу і високій активності НВК. Для лікування НАСГ у хворих на НВК доцільне використання есенціальних фосфоліпідів.

The combination of fatty liver and increased gamma-glutamyl transpeptidase levels as a risk factor for atherosclerotic plaque development in apparently healthy people

Background/aimTo elucidate how the combination of fatty liver and increased serum gamma-glutamyl transpeptidase (GGT) levels influences atherosclerotic plaque development in apparently healthy people.Materials and methodsThe study population included people who had received an annual health checkup for more than 7 years and had no evidence of carotid plaque at baseline. We investigated the risk factors for carotid plaque occurrence using the Cox proportional hazards model.ResultsA total of 107 people (76 men and 31 women; median age, 49 years) were enrolled. At baseline, fatty liver and a serum GGT level ≥50 U/L were observed in 13 and 38 people, respectively. During a median follow-up period of 13.3 years, carotid plaques appeared in 34 people. Multivariate analysis revealed that the combination of fatty liver and a serum GGT level ≥50 U/L was the only significant risk factor for carotid plaque occurrence (age- and sex-adjusted hazard ratio: 5.55; 95% confidence interval 1.70–18.14; P = 0.005).ConclusionThe combination of fatty liver and increased serum GGT levels raises the risk for atherosclerotic plaque development in apparently healthy people.

Influence of breed on the clinical and hemato-biochemical parameters in sheep experimentally infected with Leptospira sp.

Early diagnosis of leptospirosis may aid in a favorable prognosis in infected animals, but there are few reports of clinical and hematochemical changes in the ovine species, nor whether the breed exerts any influence on the response to infection. Thus, the objective of the present study was to evaluate the clinical, biochemical and hematological alterations in Santa Inês and crossbred ewes challenged with Leptospira interrogans serogroup Pomona serovar Kennewicki. Twenty-four sheep were used in this experiment, 12 crossbred (group A) and 12 Santa Inês (group B). In each group, sheep were conjunctivally and intraperitoneally challenged. During 60 days post-infection the ewes were evaluated for the presentation of clinical signs and the blood was collected for hemogram and serum biochemistry. Concentration of urea and creatinine; serum aspartate aminotransferase activity (AST); gamma-glutamyltransferase (GGT); total protein and albumin; total bilirubin, direct and indirect were analyzed. The urine of these sheep was collected for urinalysis. Only two Santa Inês sheep showed blood in the urine. Clinical signs implicated in Leptospira sp. infection were not identified. Some sheep had anemia, especially crossbred. However, anemia may be attributed to the more effective cellular response that has been identified in crossbred animals. Only one animal presented leukocytosis with neutrophilia, while 11 presented atypical leukopenia, especially those of the Santa Inês breed. There was a decrease in total protein and albumin, as well as the increase in gammaglutamyltranspeptidase (GGT), especially in Santa Inês sheep. The level of aspartate aminotransferase (AST) remained within the normal range for the species. A significant increase (p < 0.05) in conjugated bilirubin levels in challenged animals was detected. Only one sheep intraperitoneally challenged presented a high level of urea in the blood, but the creatinine level remained within the normal range. The intraperitoneal route was responsible for more significant changes (p < 0.05) in the hemogram and biochemistry when compared to the conjunctival route. The results indicate that crossbred sheep have a more efficient cellular response than Santa Inês sheep, which may confer a greater resistance to infection. Clinical signs are not good parameters to follow the development of leptospirosis in crossbred and Santa Inês breed. Hematological and biochemical analyzes were useful in the detection of anemia and possible liver changes caused by leptospirosis. The intraperitoneal route was able to cause more conclusive alterations of the analyzed parameters, however, it is possible that the alterations caused by the conjunctival route reproduce in a more faithful way what happens in a natural situation of infection.

Hepatobiliary cystadenomas with and without biliary leak

Background: The incidence of benign tumors such as biliary cystadenoma is very low, its finding is generally incidental. The definitive diagnosis is anatomopathological. Histologically, 3 types of cystadenomas are defined, the first with mesenchymal stroma similar to ovarian tissue, it is the most frequent in women. The second with absence of mesenchymal is more frequent in men. The third and rarer type also has no mesenchymal stroma and instead has eosinophilic epithelial cells. Despite the improvement in imaging tests, differential diagnosis is sometimes difficult and may be confused, as in the first case, with simple cysts or with hydatid cystst. Methods: Clinical Case 1 - Female, 41 years old. Multiple consultations for pain in HD, Fever, coluria in the last 8 months. Physical examination without particularities. Functional Hepatic: only the increase in Gammaglutamyltranspeptidase (GGT) stands out. Clinical case 2 - Female, 54 years old, recurrent vesicular colic, echo of abdomen: vesicular lithiasis, polylobulated cyst, segment VI. Tomography: segment VI well defined cystic lesion, with polylobulated contours, measures 31 x 41 x 41 mm. Results: Case 1: Ultrasound: Vesicle without lithiasis, no dilation of the bile duct. Tomography: right lobe, cystic image 60 mm, echogenic walls with sediment slope. Serology for positive hydatidosis. Initial diagnosis: hepatic echinococcosis The surgery: Cyst 5 - 6 cm. Sectors in communication with posterolateral bile duct. Walls 3-4 mm not calcified. Endothelium coating. Biliary purulent content + microlithiasis. Case 2: In its interior multiple septa that seem to converge towards its center, no nodular sectors or calcium are visualized inside. Fine bile way. Initial diagnosis: Symptomatic cystic tumor Surgery: Segmentectomy VI. In these two cases the pathological anatomy certifies: mucinous cystadenomas. Conclusion: The suspicion of hepatic cystadenoma is fundamental in the therapeutic, are infrequent tumors less than 5%, and its malignant potential makes this surgery indicated. Normality in tumor markers such as CA19-9 and carcinoembryonic antigen does not exclude the diagnosis. Rule out differential diagnoses as in our first case, hepatic echinococcosis. Major hepatectomies or lobectomies should be taken into consideration depending on the tumor location and resulting hepatic reserve. Not indicating another type of minor surgical treatment, such as drainage or unroofing of the lesion, due to the high probability of recurrence or to that it is a malignant lesion after the complete histological study of the piece.

Not only Alagille syndrome. Syndromic paucity of interlobular bile ducts secondary to HNF1\u03b2 deficiency: a case report and literature review

Backgroundpaucity of interlobular bile ducts is an important observation at liver biopsy in the diagnostic work-up of neonatal cholestasis. To date, other than in the Alagille syndrome, syndromic paucity of interlobular bile ducts has been documented in four cholestatic neonates with HFN1β mutations. A syndromic phenotype, known as renal cysts and diabetes syndrome (RCAD), has been identified. This is usually characterized by a wide clinical spectrum, including renal cysts, maturity-onset diabetes of the young, exocrine pancreatic insufficiency, urogenital abnormalities and a not well established liver involvement. Herein we report a novel case of paucity of interlobular bile ducts due to an HFN1β defect.Case presentationA 5-week-old boy was admitted to our department for cholestatic jaundice with increased gamma-glutamyl transpeptidase and an unremarkable clinical examination. He had been delivered by Caesarian section at 38 weeks’ gestation from unrelated parents, with a birth weight of 2600 g (3rd percentile). Screening for cholestatic diseases, including Alagille syndrome, was negative except for a minor pulmonary artery stenosis at echocardiography and a doubt of a thoracic butterfly hemivertebra. The finding of hyperechogenic kidneys with multiple bilateral cortical cysts at ultrasound examination, associated with moderately impaired renal function with proteinuria, polyuria and metabolic acidosis, was suggestive of ciliopathy. A liver biopsy was performed revealing paucity of interlobular bile ducts, thus the diagnosis of Alagille syndrome was reconsidered. Although genetic tests for liver cholestatic diseases were performed with negative results for Alagille syndrome (JAG1 and NOTCH2), a de-novo missense mutation of HNF1β gene was detected. At 18 months of age our patient has persistent cholestasis and his itching is not under satisfactory control.ConclusionsAlagille syndrome may not be the only syndrome determining paucity of interlobular bile ducts in neonates presenting with cholestasis and renal impairment, especially in small for gestational age newborns. We suggest that HNF1β deficiency should also be ruled out, taking into consideration HNF1β mutations, together with Alagille syndrome, in next generation sequencing strategies in neonates with cholestasis, renal impairment and/or paucity of interlobular bile ducts at liver biopsy.

Pyogenic Liver Abscess: Does Escherichia Coli Cause more Adverse Outcomes than Klebsiella Pneumoniae?

This paper aims to demonstrate if Escherichia coli pyogenic liver abscess (ECPLA) results in adverse outcomes compared to Klebsiella pneumoniae PLA (KPPLA). A retrospective review of all patients admitted at a tertiary hospital in Singapore from 2003 to 2011 was performed. Patients with age <18 years, amoebic liver abscess, infected liver cyst, culture negative abscess or ruptured liver abscess requiring urgent surgical intervention were excluded. Only patients with blood or pus culture confirmation of ECPLA (n = 24) or KPPLA (n = 264) were included. Median length of hospital stay, failure of non-operative therapy and 30-day mortality are the reported outcomes. ECPLA affects older patients (68 vs. 62 years, p = 0.049). Ischemic heart disease was more common in ECPLA (29 vs. 14 %, p = 0.048) and there was no difference in diabetic state (42 vs. 38 %, p = 0.743). ECPLA is more commonly associated with hyperbilirubinemia (60 vs. 34 µmol/L, p = 0.003), increased gamma-glutamyl transpeptidase (236 vs. 16 IU/L, p = 0.038) and gallstones (58 vs. 30 %, p = 0.004). KPPLA are larger in size (6 vs. 4 cm, p = 0.006) and had percutaneous drainage (PD) more frequently (64 vs. 42 %, p = 0.034). There was no difference in median hospital stay (14 vs. 14 days, p = 0.110) or 30-day mortality (17 vs. 10 %, p = 0.307) between ECPLA and KPPLA. Among patients with ECPLA, antibiotic treatment with PD appeared to have higher mortality compared to antibiotic treatment alone (30 vs. 7 %) but this was not significant (p = 0.272). In the setting of multimodal care, outcomes of ECPLA are comparable to KPPLA.

PP.22.15

Objective: Recently the impact of acute decompensated heart failure (ADHF) on hepatic function has been described as cardio-hepatic syndrome. It is assumed that cytolysis is mainly associated with systemic hypoperfusion, whereas cholestasis - with volume overload. Systemic congestion is the known main driver for morbidity, mortality and hospital readmission of patients with ADHF. The aim of this study was to determine possible association of impaired liver function tests (LFT) with hydration status in patients with ADHF. Design and method: In 200 patients with ADHF (84 male, 72.9 ± 10.7 years(M ± SD), arterial hypertension 79%, myocardial infarction 43%, atrial fibrillation (AF) 62%, diabetes mellitus 36.5%, chronic kidney disease (CKD) 38%, anaemia 23.5%, chronic obstructive lung disease 23.5%, ejection fraction(EF) 45 ± 12%, EF < 35% 25%, chronic hepatic diseases 9.5%) alanine transaminase(ALT), aspartate transaminase(AST), total bilirubin, alkaline phosphatase (AP), gamma-glutamyl transpeptidase(GGT) were measured and hydration status by bioimpedance vector analysis (BIVA) was assessed using resistance(R) and reactance(Xc), standardized by height(h). LFTs were considered abnormal when levels exceeded local upper normal levels. Mann-Whitney and Spearman test were performed. P < 0.05 was considered statistically significant. Results: Increase of ALT and/or AST occurred in 29 (14.5%) patients (alone ALT/ alone AST/ both TA – in 42.3, 19.2, 38.5% respectively), increase of bilirubin,AP and GGT - in 68(34%), 14(7%), 20(10%) patients respectively. Patients with versus without transaminases increase had higher rate of signs of congestion: echo-hydropericardium (33 vs 12%, p < 0.01), radiological signs of hydrothorax (72 vs 32%, p < 0.001), jugular venous distension (55 vs 21%, p < 0.001). The patients with versus without increase of bilirubin demonstrated higher volume overload: lower levels of both R/h and Xc/h (218 ± 44 vs 238 ± 54 Om/m, p < 0.01 and 16 ± 7 vs 19 ± 8 Om/m, p < 0.01). Negative correlations between serum bilirubin and BIVA parameters of hyperhydration were revealed (r = −0.38 for R/h and r = −0.29 for Rx/h, p < 0.05). Conclusions: Impaired LFT were common in patients with ADHF and were associated with signs of congestion (hydropericardium, hydrothorax, jugular venous distension). Increase of bilirubin was associated with higher volume overload assessed by BIVA. The results of the study suggest that congestion may be important in the development of cardiohepatic syndrome in patients with ADHF.

P17.32 * EFFICACY AND TOLERABILITY OF BEVACIZUMAB MONOTHERAPY IN PATIENTS WITH PREVIOUSLY TREATED RECURRENT GLIOBLASTOMA MULTIFORME (GBM)

INTRODUCTION: Glioblastoma Multiforme (GBM) represents the most common and malignant form of brain tumor. GBMs are highly vascularized and their cells frequently express the vascular endothelial growth factor (VEGF) receptor. VEGF has a key role in stimulating angiogenesis and enhancing intratumoral vascular permeability. Bevacizumab is a humanized monoclonal antibody which inhibits VEGF and tumor cell growth. Data from the literature show that this drug has a different toxicity profile, pattern of response, and relapse rate in comparison with alchilant agents. PATIENTS AND METHODS: The aim of this study was to evaluate the efficacy and tolerability of Bevacizumab in patients with GBM progressed after prior treatments (STUPP and FTM protocols) and with adequate bone marrow, renal, and hepatic function and Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0-2. The drug was administered as monotherapy every 14 days as an intravenous infusion at the dose of 10 mg/kg until recurrence and/or clinical-radiological progression. Brain magnetic resonance imaging (MRI) scans were performed every 60 days and treatment response was defined according to the McDonald criteria. Toxicity was assessed using the NCI CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0. RESULTS: From October 2009 to March 2014, we analyzed 15 patients, 8 males (53.3%) and 7 females (46.7%), with a median age of 54.8 years (range 36-70, 4 were over 65 years old); nine (60%) and six (40%) patients had an ECOG PS of 1 and 2, respectively. The median number of cycles administered was 14.3 (range 2-62). Median progression-free survival (PFS) was 130 days (average PFS was 201.8 days). Six patients showed a survival benefit of 12, 12, 10, 8, 17 and 31 months, a partial response and a stable disease were observed in the last three of them, respectively. Disease control rate (DCR) was 53.3%. Bevacizumab was generally well tolerated. Particularly, hematological toxicity, commonly of grade 1, was observed as leucopenia in 40% of cases, while the most common non-hematological side effects were grade 1 increase of gamma glutamyl transpeptidase (GGT) levels (33.3%), fatigue (20%), and proteinuria (20%). CONCLUSIONS: Although our limited sample size does not permit definitive conclusions, Bevacizumab monotherapy appears to be a safe and effective treatment option for recurrent GBM, with a good clinical-radiological response and an increased PFS in most patients.

Biochemical Profiling Study in Umbilical Cord Blood as Predictors of Neonatal Damage

Background : During pregnancy inflammatory, metabolic and immunologic disorders that affect differently the fetus, are known. These could be early disorders: abortion, intrauterine growth retardatio n, low birth weight and neonatal death; or late disorders: cardiovascular and metabolic disease in adults. The objective was to analyze different biochemical parameter s i n maternal venous blood and newbor n’s umbilical cord blood (UCB) from healthy and pathological mothers for early detection of future perinatal complications. Methods: Maternal venous blood (283) and UCB (283) were analyzed. The patients were consecutively, prospectively and transversally studied. Delivery: cesarean section. Mothers and newborns were classified: control group (C) (n = 99) and pathological group (P) (n = 184). Glucose, urea, creatinine, uric acid (UA), bilirubin (Bi), proteins (PT), albumin (Alb), transaminases (ALT/AST), alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), creatinkinasa (CK), lactate dehydrogenase (LDH), iron, calcium, phosphorus, magnesium, sodium, potassium (K), chlorine, cholesterol (Chol), triglycerides (TG) and hsCRP were determined by recommended methods. Studen t’s t and Mann-W h itney tests were applied, P &lt; 0.05. Results: P newborns from P mothers showed significant decrease: in gestation weeks (GW) and newborn weight (NW) with respect to C newborns from C mothers (P &lt; 0.001); significant increases in Chol, TG, UA, K, Bi, AST and GGT (P: 0.01, &lt; 0.001, 0.03, &lt; 0.001, 0.04, &lt; 0.001, &lt; 0.001, respectively) and significant decreases in CK, PT and Alb (P &lt; 0.001 ). P mothers showed significant increase in UA, ALT, AST, GGT (P: 0.04, 0.02, 0.04, &lt; 0.001, respectively) with respect to C mothers. Conclusions : The decrease in GW and NW in P newborns with respect to C would be related to intrauterine growth restriction (IUGR) accompanying these disorders; increases in Chol, TG, UA, K, Bi, AST and GGT would be related to cellular destruction associated to maternal disorders and deficit in pulmonary development by IUGR respectively, whereas decreases in CK, PT and Alb to IUG R. In crease in UA, ALT, AST and GGT from P mothers with respect to C would be associated to inflammatory process with liver alterations. A future study including greater number of samples and analysis of each maternal disorder is proposed to obtain early markers of neonatal damage and to prevent future perinatal complications. Int J Clin Pediatr. 2014;3(1):5-11 doi: http://dx.doi.org/10.14740/ijcp140e

Weekly Inotuzumab Ozogamicin (InO) In Adult Patients With Relapsed Or Refractory CD22-Positive Acute Lymphoblastic Leukemia (ALL)

▪ BackgroundInO is a humanized anti-CD22 antibody conjugated to calicheamicin. CD22 is expressed on a majority of B-cell ALL. An initial study suggested InO efficacy and tolerability in ALL (Cancer. 2013 Aug 1;119(15):2728-36). AimsTo optimize the InO dose and weekly schedule, and evaluate safety and efficacy in CD22+ relapsed/refractory ALL. MethodsThis phase 1, dose-escalation and expansion study enrolled pts aged ≥18 y with CD22+ refractory/relapsed ALL and no central nervous system disease. InO was administered in 28-d cycles (Table), up to 6 cycles. The final dose was to be determined based on dose-limiting toxicities (DLT) and efficacy, using the MDACC EffTox V2.10 software. Adverse event (AE) severity was assessed per CTCAE V3. DLTs included the following InO -related events in Cycle 1: gr ≥4 nonhematologic AE; prolonged myelosuppression; gr 3 nonhematologic AE >7 d; any AE resulting in permanent InO discontinuation. Complete response (CR) was defined as <5% bone marrow blasts without peripheral blasts, ANC ≥1,000/µL, platelets >100,000/µL and no extramedullary disease; CRi defined as CR without ANC or platelet recovery. ResultsWe report data for 37 pts: median age was 56 y (23-75 y); 65% were male; 17 (46%) pts were in salvage 1, 9 (24%) in salvage 2, and 10 (27%) in salvage ≥3; 7 (19%) pts had prior allogeneic stem cell transplant (SCT); 6 (16%) pts were Ph+; CD22 found on a median of 98% blasts (31.1-100%); median WBC was 5.18×103/mm3 (0.5-67.2×103/mm3). The expansion cohort (n=13) was comprised of pts with higher peripheral blast counts (PBC) and higher risk cytogenetics as compared to the dose escalation group (n=24): median PBC of 4158/µL (0-38,976/µL) and 18/µL (0-10,189/µL), respectively; aberrant baseline cytogenetics were reported in 10/13 (77%) expansion pts including 2 pts Ph+ and 2 pts t(4;11) and 11/24 (46%) escalation pts. Median follow-up in surviving pts was 4.1 mo (1-12.6 mo). Thirty-two pts discontinued InO: 14 due to PD, relapse or resistant disease, 11 proceeded to SCT, 6 due to AEs (1 pt each: gr 3 acute renal failure, gr 2 ascites, gr 2 increased gamma-glutamyl transpeptidase (GGT), gr 5 graft failure, gr 2 constitutional symptoms and gr 2 veno-occlusive disease (VOD)) and 1 to receive maintenance therapy. InO-related ≥gr 3 AEs (≥10% of pts) were thrombocytopenia (30%) and neutropenia (19%). Other ≥gr 3 hepatic AEs included increased ALT (5.4%) and increased GGT (3%). Gr 2 AEs include ascites (2 pts) and VOD (2 pts). Sixteen deaths were reported: ALL (n=11), sepsis following SCT (n=3), graft failure (n=1) and gut GVHD and liver dysfunction (n=1). The RP2D was determined as 1.8 mg/m2/cycle based on efficacy and safety in the dose escalation patients (1 DLT; 89% CR+CRi rate; all remissions were minimal residual disease (MRD) negative (<1 blast out of 104 mononuclear cells by flow cytometry) with a dose reduction to 1.6 mg/m2/cycle upon achievement of CR/CRi. The dose reduction was recommended due to AEs leading to discontinuation and the observation of increased InO exposure with successive cycles in prior studies.The remission rate (CR+CRi) for the dose escalation pts (n=24) was 79% (95% CI: 58, 93) and 46% (95% CI: 19, 75) for the dose expansion pts (n=13); 18/19 (95%) escalation pts with CR/CRi and 4/6 (67%) expansion pts with CR/CRi achieved MRD negativity. Overall, the median time to remission and MRD negativity was 29 d (20-85d) and 34 d (22-141d), respectively. Minimum InO concentrations in responders were higher than in pts failing treatment. Summary/ConclusionThe RP2D was confirmed as 1.8 mg/m2/cycle, InO had a tolerable safety profile primarily characterized by hematologic, gastrointestinal and hepatic AEs. Single-agent InO demonstrated encouraging clinical activity in this relapsed/refractory population; preliminary efficacy results appear dynamically related to exposure and circulating blasts. Further exploration in CD22+ ALL is ongoing. [Display omitted] Disclosures:DeAngelo:Pfizer Inc: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This abstract presents findings from a phase I study of inotuzumab ozogamicin in patients with relapsed/refractory CD22+ acute lymphoblastic leukemia; this drug is investigational and is not approved for use in any indication in any country. Stock:Pfizer Inc: Research Funding. Liedtke:Millennium: The Takeda Oncology Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Schiffer:Amgen Inc: Research Funding; Pfizer Inc: Research Funding. Ananthakrishnan:Pfizer Inc: Employment. Boni:Pfizer Inc: Employment. Luu:Pfizer Inc: Employment. Liau:Pfizer Inc: Employment. Vandendries:Pfizer Inc: Employment. Advani:Pfizer Inc: Research Funding.

Phase I/II Study of Hepatic Arterial Infusion Chemotherapy With Gemcitabine in Patients With Unresectable Intrahepatic Cholangiocarcinoma (JIVROSG-0301)

No established therapy exists for unresectable intrahepatic cholangiocarcinoma (ICC). We conducted a phase I/II study to ascertain the recommended dose (RD) of hepatic arterial infusion using gemcitabine (GEM) for ICC and to assess the efficacy and safety. For patients with unresectable ICC, GEM was administered through the hepatic artery via the port system as a 30-minute infusion on days 1, 8, and 15 every 4 weeks for 5 cycles. In phase I, dosage for levels 1, 2, and 3 was set at 600, 800, and 1000 mg/m, respectively, and was increased in 3 to 6 patients at a time. Maximum tolerated dose was defined as a dosage resulting in dose-limiting toxicity in 2 of 3 patients or 3 of 6 patients, and RD was estimated during the first cycle. In the phase II, more RD patients were added to assess tumor response and toxicity. During the phase I, 16 patients were enrolled. Maximum tolerated dose was not reached. Assuming RD at 1000 mg/m, the phase II enrolled a total of 13 patients. The following Grade 3 toxicities were observed: neutropenia 20%, increased gamma-glutamyl transpeptidase 8%, increased aspartate aminotransferase 4%, increased alanine aminotransferase 4%, increased bilirubin 4%, nausea 4%, and fatigue 4%. The tumor response rate was 7.7% (complete response 0, partial response 1, stable disease 8, and progressive disease 4). Whereas the toxicity of hepatic arterial infusion with 1000 mg/m GEM for ICC was tolerable, expected efficacy could not be obtained, thus suggesting only minimal activity.

Pharmacokinetics, Safety, and Tolerability of Voriconazole in Immunocompromised Children

The pharmacokinetics of voriconazole in children receiving 4 mg/kg intravenously (i.v.) demonstrate substantially lower plasma exposures (as defined by area under the concentration-time curve [AUC]) than those in adults receiving the same therapeutic dosage. These differences in pharmacokinetics between children and adults limit accurate prediction of pediatric voriconazole exposure based on adult dosages. We therefore studied the pharmacokinetics and tolerability of higher dosages of an i.v.-to-oral regimen of voriconazole in immunocompromised children aged 2 to <12 years in two dosage cohorts for the prevention of invasive fungal infections. The first cohort received 4 mg/kg i.v. every 12 h (q12h), then 6 mg/kg i.v. q12h, and then 4 mg/kg orally (p.o.) q12h; the second received 6 mg/kg i.v. q12h, then 8 mg/kg i.v. q12h, and then 6 mg/kg p.o. q12h. The mean values for the AUC over the dosing interval (AUCτ) for 4 mg/kg and 6 mg/kg i.v. in cohort 1 were 11,827 and 22,914 ng.h/ml, respectively, whereas the mean AUCτ values for 6 mg/kg and 8 mg/kg i.v. in cohort 2 were 17,249 and 29,776 ng.h/ml, respectively. High interpatient variability was observed. The bioavailability of the oral formulation in children was approximately 65%. The safety profiles were similar in the two cohorts and age groups. The most common treatment-related adverse event was increased gamma glutamyl transpeptidase levels. There was no correlation between adverse events and voriconazole exposure. In summary, voriconazole was tolerated to a similar degree regardless of dosage and age; the mean plasma AUCτ for 8 mg/kg i.v. in children approached that for 4 mg/kg i.v. in adults, thus representing a rationally selected dosage for the pediatric population.

Clinical factors influencing liver stiffness as measured by transient elastography (Fibroscan®) in patients with chronic liver disease

Transient elastography as performed using the Fibroscan is a useful noninvasive method for evaluating hepatic fibrosis. However, recent studies have found that liver stiffness measurement (LSM) values are inappropriately elevated in acute hepatitis or in the acute flare state of chronic hepatitis, suggesting that the LSM value obtained by the Fibroscan is not a reliable marker for fibrosis. We retrospectively evaluated the clinical factors influencing the LSM value obtained using transient elastography as performed using the Fibroscan in patients with chronic liver disease. A total of 298 patients who were followed in Kungpook National University Hospital from November 2007 to May 2008 due to previously established liver cirrhosis or chronic liver disease were investigated using the Fibroscan, laboratory test, ultrasound, and/or abdominal computed tomography. The 298 patients were aged 47.8+/-12.9 years (mean+/-SD). The cut-off value for a diagnosis of liver cirrhosis was 12.5 kPa (as used in previous studies). Thirty-six patients (15%) and 202 patients (85%) with chronic liver disease without clinical manifestation of cirrhosis had LSMs of >12.5 kPa and <12.5 kPa, respectively. Multivariate analysis revealed that LSM values were unusually increased in patients with chronic liver disease who were older (P=0.007) or who had increased gamma glutamyltranspeptidase (GGT) (P=0.022), decreased albumin (P=0.015), or increased total bilirubin (P=0.009). This study reveals that age, GGT, and albumin are clinical factors influencing LSM values. This reinforces the need to interpret LSM values in the context of a defined diagnosis, biochemical data, radiologic examination, and other clinical findings.

Pharmacological inhibition of integrin αvβ3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis

The vitronectin receptor integrin alphavbeta3 promotes angiogenesis by mediating migration and proliferation of endothelial cells, but also drives fibrogenic activation of hepatic stellate cells (HSCs) in vitro. Expecting antifibrotic synergism, we studied the effect of alphavbeta3 inhibition in two in vivo models of liver fibrogenesis. Liver fibrosis was induced in rats by way of bile duct ligation (BDL) for 6 weeks or thioacetamide (TAA) injections for 12 weeks. A specific alphavbeta3 (alphavbeta5) inhibitor (Cilengitide) was given intraperitoneally twice daily at 15 mg/kg during BDL or after TAA administration. Liver collagen was determined as hydroxyproline, and gene expression was quantified by way of quantitative polymerase chain reaction. Liver angiogenesis, macrophage infiltration, and hypoxia were assessed by way of CD31, CD68 and hypoxia-inducible factor-1alpha immunostaining. Cilengitide decreased overall vessel formation. This was significant in portal areas of BDL and septal areas of TAA fibrotic rats and was associated with a significant increase of liver collagen by 31% (BDL) and 27% (TAA), and up-regulation of profibrogenic genes and matrix metalloproteinase-13. Treatment increased gamma glutamyl transpeptidase in both models, while other serum markers remained unchanged. alphavbeta3 inhibition resulted in mild liver hypoxia, as evidenced by up-regulation of hypoxia-inducible genes. Liver infiltration by macrophages/Kupffer cells was not affected, although increases in tumor necrosis factor alpha, interleukin-18, and cyclooxygenase-2 messenger RNA indicated modest macrophage activation. Specific inhibition of integrin alphavbeta3 (alphavbeta5) in vivo decreased angiogenesis but worsened biliary (BDL) and septal (TAA) fibrosis, despite its antifibrogenic effect on HSCs in vitro. Angiogenesis inhibitors should be used with caution in patients with hepatic fibrosis.

An Early Increase in Gamma Glutamyltranspeptidase And Low Aspartate Aminotransferase Peak Values Are Associated With Superior Outcomes After Orthotopic Liver Transplantation

Background Prediction of prognosis after liver transplantation (OLT) remains difficult. The present study determines if standard laboratory parameters measured within the first week after OLT correlate with outcome. Patients and Methods Laboratory parameters measured within the first weak after OLT of 328 patients were grouped either graft loss or death within 90 days after (group 1: graft loss; group 2: death; group 3: neither graft loss nor death within 90 days). Results Peak AST and ALT were significantly lower in group 3 (1867 and 1252 U/L) than in group 1 (4474 and 2077 U/L) or 2 (3121 and 1865 U/L). Bilirubin was significantly lower and γ-GT significantly higher in group 3 compared to groups 1 and 2. In multivariate analysis, high AST peaks were independently associated with death or graft loss within 90 days. An increase in γ-GT and low bilirubin early after transplantation were found to be independently associated with superior outcome. Discussion Unexpectedly, a disproportionate rise in γ-GT was associated with graft and patient survival of more than 90 days. This might be explained by regeneration phenomena in the liver indicative of a well functioning graft.

Alcohol Consumption by Cirrhotic Subjects: Patterns of Use and Effects on Liver Function

We investigated patterns of use of alcohol and its clinical effects among cirrhotic subjects who participated in a randomized clinical trial comparing the efficacy of transjugular intravenous portosystemic shunt and distal splenorenal shunt. There were 132 cirrhotic subjects, 78 with alcoholic liver disease (ALD), who were followed for a median of 49 months (range 2-93 months). Alcohol use was assessed by patient questionnaire, with corroboration by family members. Twenty-eight subjects (21%) were drinking at study entry and 60 subjects (45%) drank during follow-up. Heavy drinking (>4 drinks/day) was recorded in 25 ALD subjects, but in no non-ALD subjects (P < 0.0001). Drinking by ALD subjects was associated with a 153% increase in gamma-glutamyl transpeptidase (GGT) (P < 0.0001). The frequencies of death (46%vs 30%), ascites (33%vs 20%), encephalopathy (56%vs 42%), and variceal bleeding (11%vs 3%) were greater in the ALD group. In a Cox proportional hazards model only "ever heavy drinking" was associated with death (P= 0.0099), while recent heavy drinking increased the hazard of variceal hemorrhage dramatically (odds ratio 10.85). Whereas most cirrhotic subjects, alcoholic or not, did not drink during 5 yr of observation, heavy alcohol use occurred exclusively in ALD patients. Alcohol use by ALD subjects was associated with elevations in GGT and was linked to death and with rebleeding from shunt dysfunction.