Hepatic Reserves Research Articles

Effects of rosmarinic acid on acetaminophen-induced hepatotoxicity in male Wistar rats

Context: Drug-induced liver injury is a significant worldwide clinical problem. Rosmarinic acid (RA), a natural phenol, has antioxidant effects. Objective: The effects of RA against acetaminophen (N-acetyl-p-amino-phenol (APAP))-induced oxidative damage and hepatotoxicity in rats were investigated. Materials and methods: Male Wistar rats were pretreated with RA (10, 50 and 100 mg/kg, i.g.) for one week. On day 7, rats received APAP (500 mg/kg, i.p.). Then aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, total protein, malondialdehyde (MDA), glutathione (GSH), total antioxidant capacity (TAC), glutathione S-transferase (GST), cytochrome CYP450 and histopathological changes were determined. Results: APAP-induced oxidative stress in liver by a significant increase in the level of MDA (7.6 ± 0.21 nmol/mg) as well as a decrease in the contents of TAC (1.75 ± 0.14 μmol/g), GSH (1.9 ± 0.22 μmol/g) and GST) 3.2 ± 0.28 U/mg). RA treatment decreased MDA (4.32 ± 0.35 nmol/mg) but increased the contents of TAC (3.51 ± 0.34 μmol/g), GSH (3.42 ± 0.16 μmol/g) and GST (5.71 ± 0.71 μmol/g) in APAP group. RA 100 mg/kg decreased ALT (91.5 ± 1.5 U/L), AST (169 ± 8.8 U/L) and CYP450 (3 ± 0.2 nmol/min/mg) in APAP group. Histologically RA attenuated hepatic damage by decreasing necrosis, inflammation, and haemorrhage in liver sections of APAP group. Discussion and conclusions: This is the first report that oral administration of RA dose-dependently elicited significant hepatoprotective effects in rats through inhibition of hepatic CYP2E1 activity and lipid peroxidation. RA-protected hepatic GSH and GST reserves and total tissue antioxidant capacity.

Serum cholinesterase: A predictive biomarker of hepatic reserves in chronic hepatitis D.

AIMTo determine the predictive performance of cholinesterase compared to existing prognostic models in evaluating liver function in patients with chronic hepatitis D.METHODSIn an observational, cross-sectional and retrospective study, consecutive patients with hepatitis D cirrhosis were evaluated. Demographic, clinical and laboratory parameters were recorded. Serum cholinesterase levels were correlated with existing scoring models for chronic liver disease and Liver function tests. Receiver operating characteristic (ROC) curves were constructed to find an optimal cholinesterase level predicting ascites, Child Turcotte Pugh (CTP) score ≥ 10, model for end stage liver disease (MELD) score ≥ 15, baseline-event-anticipation (BEA) score for hepatitis D ≥ 5 and the aspartate transaminase to Platelet Ratio Index (APRI) ≥ 1.5.RESULTSThis study investigated 233 patients with chronic liver disease due to hepatitis D; 192 were male, median age 42 (16-69 years). Fifty patients had ascites and 15 had encephalopathy. One hundred and sixty-seven (71.7%) were in Child class A, 52 (22.3%) in Child class B and 14 (5.0%) in class C. A MELD score of 15 or more was seen in 24 patients. Cholinesterase levels correlated well with the INR, albumin, CTP score, MELD, MELD sodium, BEA and APRI scores (P < 0.001 each). Area under the ROC curve for ascites, CTP ≥ 10, MELD ≥ 15, BEA ≥ 5, APRI ≥ 1.5 was 0.836, 0.966, 0.913, 0.871 and 0.825 respectively (P < 0.001 each). Cut off values of cholinesterase (IU/L) for predicting ascites, CTP ≥ 10, MELD ≥ 15, BEA ≥ 5 and APRI ≥ 1.5 were < 3812, < 2853, < 2829, < 4719 and < 3954 with a sensitivity of 80%, 100%, 91.67%, 82.50%, 58.0% and specificity of 81.97%, 84.79%, 87.56%, 77.06% and 55.64% respectively.CONCLUSIONSerum cholinesterase demonstrates promising correlations with serum albumin, INR and CTP, MELD, BEA and APRI scores and is predictive of liver reserves in hepatitis D cirrhosis.

THU-153 - Serum cholinesterase: a predictive biomarker of hepatic reserves in patients with chronic Hepatitis D

THU-153 - Serum cholinesterase: a predictive biomarker of hepatic reserves in patients with chronic Hepatitis D

Current Expectations for Cardiac Transplantation in Patients With Congenital Heart Disease.

Congenital heart disease accounts for 40% of pediatric heart transplants and presents unique challenges to the transplant team. Suitability for transplantation is defined in part by degree of sensitization, pulmonary vascular resistance, and hepatic reserves. The incremental transplant risk for patients with congenital heart disease occurs within the first 3 months, after which survival is equivalent to transplantation for cardiomyopathy. Single ventricle with prior palliation, and especially the failing Fontan, carry the highest risk for transplantation and are least amenable to bridging with mechanical circulatory support. More effective bridging to transplant with mechanical circulatory support will require improvements in the adverse event profile of available pumps and the introduction of miniaturized continuous flow technology. The major barriers to routine long-term survival are chronic allograft failure and allograft vasculopathy. Despite these many challenges, continuing improvements in the care of pediatric heart transplant patients have pushed the median posttransplant survival past 15 years for children and to 20 years for infants.

Aspect of reproductive biology of the cassava croaker, Pseudotolithus senegalensis (valenciennes, 1833) of Ivory coast continental shelf

From January to December 2014, some aspects of Pseudotolithus senegalensis reproductive biology in Ivory coast were investigated and focused on sex ratio, gonadosomatic and liver-somatic index, size at first maturity, stages of gonadal development and fecundity. A total of 696 fish with body length of 12 to 36 cm standard length (SL) and body weight of 25. 2 to 675.1 g were used for this study. The sex ratio of P. senegalensis was 1: 0.5 (male to female). The females were more than the males (x 2 0,05 (1) = 51.36; p< 0,05). Males and females reach first maturity at 19.01 and 22.28 cm SL respectively. The monthly variations of the gonadosomatic index (GSI), hepatosomatic index (HIS) and the condition factor (K) indicated two periods of reproduction. The long period and the short period were respectively from March to June and from September to November. The hepatic reserves seem to be mobilized to ensure the energetic cost of the reproduction. The absolute Fecundity was ranged from 78612 to 140946 eggs and was positively correlated with standard length and weight. Fecundity-length and fecundity-weight relationships showed positive correlations. The fecundity-length and fecundity-weight relationships were determined by regression analysis with the regression equation F= 12.820xSL– 321.70 (r=0.99) for fecundity-length and F= 0.27xTW – 46.66 (r=0.98) for fecundity-weigth relationship.

Altered bioenergetics and developmental effects in striped marsh frog (Limnodynastes peronii) tadpoles exposed to UV treated sewage

Effectively treating domestic wastewater so that it can be safely discharged or reused is critical for maintaining the integrity of freshwater resources, and for protecting the health of animals that rely on these systems. Amphibians are currently facing widespread population declines, so there is a particularly urgent need to investigate exposure scenarios that might result in weakened amphibian populations. Domestic sewage has received little attention as a possible factor that could influence the survival, growth and development, or general health of amphibians. However, wastewater reuse for crop irrigation and other purposes is increasing and holding ponds and constructed wetlands exist at many wastewater treatment facilities, introducing conceivable pathways that could result in the exposure of amphibians to treated wastewater. We exposed developing striped marsh frog (Limnodynastes peronii) tadpoles, to control water and 12.5, 25, 50 and 100% UV treated domestic sewage, and quantified effects on growth and development, hepatic energy reserves, and enzymatic pathways associated with detoxification and oxidative stress. Growth and development were accelerated and relative liver size was increased in exposed animals. The exposure resulted in an apparently hormetic increase in hepatic triglycerides and dose-dependent reduction in glycogen stores, as well as increased lipase and NADPH activity, indicating a general disruption to energy metabolism and/or mobilization. Contrary to expectations based on published studies with fish, we found no evidence of lipid peroxidation or induction of the detoxification enzyme Superoxide Dismutase (SOD), however, this may reflect the use of UV treatment as opposed to chlorination for disinfection. Chemical analysis and risk-based prioritization consistently identified fluoxetine, triclosan and diazinon as high-risk contaminants in the wastewater, with nonylphenol and mestranol flagged as risks during one early collection. Research is needed to explore the potential for these specific contaminants to elicit the responses identified in the present study, and to perform similar assessments using wastewater from other locations with different treatment options.

Infusion of CD133+ Bone Marrow–derived Stem Cell After Selective Portal Vein Embolization Enhances Functional Hepatic Reserves After Extended Right Hepatectomy

Lim, Chetana MD; Audollent, Raphaëlle MD; Pocard, Marc MD, PhD; Azoulay, Daniel MD, PhD Author Information

Antioxidant and Antifatigue Properties of the Aqueous Extract of Moringa oleifera in Rats Subjected to Forced Swimming Endurance Test.

The effects of the aqueous extract of Moringa oleifera on swimming performance and related biochemical parameters were investigated in male Wistar rats (130–132 g). Four groups of rats (16 per group) were fed a standard laboratory diet and given distilled water, 100, 200, or 400 mg/kg of extract, respectively, for 28 days. On day 28, 8 rats from each group were subjected to the forced swimming test with tail load (10% of body weight). The remaining 8 rats per group were subjected to the 90-minute free swim. Maximum swimming time, glycemia, lactamia, uremia, triglyceridemia, hepatic and muscle glycogen, hematological parameters, and oxidative stress parameters (superoxide dismutase, catalase, reduced glutathione, and malondialdehyde) were measured. Results. M. oleifera extract increased maximum swimming time, blood hemoglobin, blood glucose, and hepatic and muscle glycogen reserves. The extract also increased the activity of antioxidant enzymes and decreased the blood concentrations of malondialdehyde. Furthermore, it decreased blood concentrations of lactate, triglycerides, and urea. In conclusion, the antifatigue properties of M. oleifera extract are demonstrated by its ability to improve body energy stores and tissue antioxidant capacity and to reduce the tissue build-up of lactic acid.

Global Phase I/III Pharmacokinetic and Efficacy Study Comparing CT-P10, a Biosimilar Candidate to the Rituximab Reference Product in Patients with Advanced Stage Follicular Lymphoma (AFL)

Global phase I/III pharmacokinetic and efficacy study comparing CT-P10, a biosimilar candidate to the rituximab reference product in patients with advanced stage follicular lymphoma (AFL)CT-P10 is a biosimilar candidate to the reference rituximab product, EU-approved MabThera® and US-licensed Rituxan®. CT-P10 has an identical amino acid sequence and highly similar physicochemical and in vitro functional properties to its reference drug. In patients with rheumatoid arthritis (RA), CT-P10 has demonstrated compelling similarity in pharmacokinetics, pharmacodynamics, efficacy, safety and immunogenicity (http://acrannualmeeting.org/abstracts/abstract-archives/,#1736 in 2013 and #1508 in 2014).This study is a randomized, parallel-group, active-controlled, double-blind, phase I/III study designed to demonstrate similarity in pharmacokinetics and non-inferiority in efficacy of CT-P10 to rituximab when co-administered with cyclophosphamide, vincristine, and prednisone (CVP) (NCT02162771). In this international multicenter trial, 134 patients with untreated advanced stage follicular lymphoma (AFL) will be administered CT-P10 or rituximab for 24 weeks at 3 weeks intervals, defined as Core Study Period. Patients who at least achieve a partial response after the Core Study Period will continue treatment with CT-P10 or rituximab as maintenance therapy over 24 months in 2 monthly intervals (Figure 1).The patients ≥18 years, with a histologically confirmed FL of grade 1 to 3a, Ann Arbor Stage III or IV disease, at least 1 measurable tumour mass that has not previously been irradiated, confirmed CD20+ lymphoma, ECOG performance status of 0-2, and adequate bone marrow, hepatic, and renal function reserves are included.The study has been initiated at >110 clinical sites across Europe, Latin America, Asia and Africa. Currently 83 patients were enrolled in this study, and a blinded initial review of initial safety data was carried out by the Data Safety Monitoring Board. As expected from the highly similar profile of CT-P10 accomplished through analytical studies and the CT-P10 RA trial (NCT01534884, NCT01873443), preliminary safety findings in terms of adverse events (AEs), serious AEs, AEs of special interest and survival characteristics with CT-P10 in AFL patients mirror those with the historical data of rituximab reference product. As currently 4 SAEs related to a study drug (CT-P10/Rituximab) were reported and these were resolved without sequelae. Qualitative feedback from study investigators throughout all regions indicates overall positive experience. Taken together, the study provides AFL patients with early access to a biosimilar investigational product assuring improved standards of care and long-term survival outcomes.In conclusion, it is expected that this ongoing study will demonstrate that CT-P10 is well tolerated in AFL patients with a similar safety profile to the rituximab reference product. [Display omitted] DisclosuresKim:CELLTRION, Inc.: Consultancy, Honoraria. Ogura:CELLTRION, Inc.: Consultancy, Honoraria. Buske:CELLTRION, Inc.: Consultancy, Honoraria. Coiffier:CELLTRION, Inc.: Consultancy, Honoraria. Sancho:CELLTRION, Inc.: Research Funding. Jurczak:CELLTRION, Inc,: Research Funding. Kim:CELLTRION, Inc,: Research Funding. Nagarkar:CELLTRION, Inc,: Research Funding. Zhavrid:CELLTRION, Inc,: Research Funding. Hernandez Rivas:CELLTRION, Inc.: Research Funding. Vinnyk:CELLTRION, Inc.: Research Funding. Tsirigotis:CELLTRION, Inc.: Research Funding. Viero:CELLTRION, Inc.: Research Funding. Volodicheva:CELLTRION, Inc.: Research Funding. Fourie:CELLTRION, Inc.: Research Funding. Soler:CELLTRION, Inc.: Research Funding.

Hepatobiliary Quiz (Answers)—15 (2015)

Hepatobiliary Quiz (Answers)—15 (2015)

Investigating the effects of an oral fructose challenge on hepatic ATP reserves in healthy volunteers: A 31P MRS study

Impaired homeostasis of hepatic ATP has been associated with NAFLD. An intravenous fructose infusion has been shown to be an effective challenge to monitor the depletion and subsequent recovery of hepatic ATP reserves using (31)P MRS. The purpose of this study was to evaluate the effects of an oral rather than intravenous fructose challenge on hepatic ATP reserves in healthy subjects. Self-reported healthy males were recruited. Following an overnight fast, baseline liver glycogen and lipid levels were measured using Magnetic Resonance Spectroscopy (MRS). Immediately after consuming a 500ml 75g fructose drink (1275kJ) subjects were scanned continuously for 90min to acquire dynamic (31)P MRS measurements of liver ATP reserves. A significant effect on ATP reserves was observed across the time course (P<0.05). Mean ATP levels reached a minimum at 50min which was markedly lower than baseline (80±17% baseline, P<0.05). Subsequently, mean values tended to rise but did not reach statistical significance above minimum. The time to minimum ATP levels across subjects was negatively correlated with BMI (R(2)=0.74, P<0.005). Rates of ATP recovery were not significantly correlated with BMI or liver fat levels, but were negatively correlated with baseline glycogen levels (R(2)=0.7, P<0.05). Depletion of ATP reserves can be measured non-invasively following an oral fructose challenge using (31)P MRS. BMI is the best predictor of postprandial ATP homeostasis following fructose consumption.

Riboflavin (vitamin B-2) reduces hepatocellular injury following liver ischaemia and reperfusion in mice

Riboflavin has been shown to exhibit anti-inflammatory and antioxidant properties in the settings of experimental sepsis and ischaemia/reperfusion (I/R) injury. We investigated the effect of riboflavin on normothermic liver I/R injury. Mice were submitted to 60min of ischaemia plus saline or riboflavin treatment (30μmoles/kgBW) followed by 6h of reperfusion. Hepatocellular injury was evaluated by aminotransferase levels, reduced glutathione (GSH) content and the histological damage score. Hepatic neutrophil accumulation was assessed using the naphthol method and by measuring myeloperoxidase activity. Hepatic oxidative/nitrosative stress was estimated by immunohistochemistry. Liver endothelial and inducible nitric oxide synthase (eNOS/iNOS) and nitric oxide (NO) amounts were assessed by immunoblotting and a chemiluminescence assay. Riboflavin significantly reduced serum and histological parameters of hepatocellular damage, neutrophil infiltration and oxidative/nitrosative stress. Furthermore, riboflavin infusion partially recovered hepatic GSH reserves and decreased the liver contents of eNOS/iNOS and NO. These data indicate that riboflavin exerts antioxidant and anti-inflammatory effects in the ischaemic liver, protecting hepatocytes against I/R injury. The mechanism of these effects appears to be related to the intrinsic antioxidant potential of riboflavin/dihydroriboflavin and to reduced hepatic expression of eNOS/iNOS and reduced NO levels, culminating in attenuation of oxidative/nitrosative stress and the acute inflammatory response.

Divergent Hypoxia Tolerance in Adult Males and Females of the Plainfin Midshipman (Porichthys notatus)

In the summer, the plainfin midshipman (Poricththys notatus) migrates to reproduce in the nearshore environment, where oxygen levels are influenced by the tidal cycles. Parental males establish nests under rocks in the intertidal zone, where they reside until the eggs they guard are fully developed. In contrast, females and sneaker males leave the nests shortly after spawning. We examined the physiological resistance and metabolic response of parental male and female adult midshipman to hypoxia to test whether they exhibited sex-specific differences reflecting their reproductive strategies. Further, we assessed whether metabolic enzymes and metabolites were differentially enriched in tissues of parental males and females to explain the differences observed in their hypoxia tolerance. While parental males and females exhibited similar depression of their oxygen consumption in response to graded hypoxia, parental males could withstand significantly longer exposures to severe hypoxic stress. At the biochemical level, parental males showed higher hepatic glycogen reserves and higher glycolytic enzyme capacities in gills and skeletal muscles than females. Although some of these enzymatic variations could be explained by differences in body size, we also observed a significant effect of sex on some of these factors. These results suggest that parental male midshipman may benefit from sexual dimorphism at the whole-organismal (larger body size) and biochemical (enzyme activities) levels, conferring on them a higher glycolytic potential to sustain the extensive hypoxia bouts they experience in nature.

Vitamin B12 supplement alleviates N′-nitrosodimethylamine-induced hepatic fibrosis in rats

Context: Altered vitamin B12 levels have been correlated with hepatotoxicity; however, further evidence is required to establish its protective role.Objective: To evaluate the effects of vitamin B12 supplement in protecting N′-nitrosodimethylamine (NDMA)-induced hepatic fibrosis in Wistar rats.Materials and methods: Hepatic fibrosis was induced by administering NDMA in doses of 10 mg/kg body weight thrice a week for 21 days. Another group received equal doses (10 mg/kg body weight) of vitamin B12 subsequent to NDMA treatment. Animals from either group were sacrificed weekly from the start of the treatment along with their respective controls. Progression of hepatic fibrosis, in addition to the effect of vitamin B12, was assessed biochemically for liver function biomarkers, liver glycogen, hydroxyproline (HP) and B12 reserves along with histopathologically by hematoxylin and eosin (H & E) as well immunohistochemical staining for α-SMA expression.Results and discussion: Elevation in the levels of aminotransferases, SALP, total bilirubin and HP was observed in NDMA treated rats, which was concomitant with remarkable depletion in liver glycogen and B12 reserves (p < 0.05). Liver biopsies also demonstrated disrupted lobular architecture, collagen amassing and intense fibrosis by NDMA treatment. Immunohistochemical staining showed the presence of activated stellate cells that was dramatically increased up to day 21 in fibrotic rats. Following vitamin B12 treatment, liver function biomarkers, glycogen contents and hepatic vitamin B12 reserves were restored in fibrotic rats, significantly. Vitamin B12 administration also facilitated restoration of normal liver architecture.Conclusion: These findings provide interesting new evidence in favor of protective role for vitamin B12 against NDMA-induced hepatic fibrosis in rats.

A low calorie morning meal prevents the decline of hepatic glycogen stores: a pilot in vivo (13)C magnetic resonance study.

Previous studies have reported a meal-induced rise in hepatic glycogen stores from baseline levels following a fast and it is generally assumed that glycogen levels rise steadily following meals throughout the day. However, measurements are normally taken in conditions that are not typical of the Western breakfast, which is relatively carbohydrate rich with a lower calorific content than most experimental test meals. As such, little is known about the normal metabolic response to a realistic, low calorie morning meal. Therefore, the aim of this pilot study was to evaluate the effects of a low dose oral glucose intake on hepatic glycogen levels following an overnight fast in healthy subjects. Glycogen levels were monitored in vivo using (13)C Magnetic Resonance Spectroscopy at baseline and hourly for 4 hours following either a 50 g glucose drink (773 kJ) or a control drink (0 kJ) given over two different visits. During the control visit hepatic glycogen levels decreased throughout the experiment with statistically significant decreases from baseline at 190 minutes (P < 0.05) and 250 minutes (P < 0.05). By contrast, the low dose glucose intake maintained glycogen concentrations with no significant decrease from baseline over 4 hours. A comparison between visits revealed that mean glycogen concentrations were significantly greater during the glucose visit (control visit, AUC = 218 ± 39 mol L(-1) min(-1); glucose visit, AUC = 305 ± 49 mol L(-1) min(-1); P < 0.05). Liver volume decreased significantly from baseline at 180 minutes (P < 0.05) post consumption in both groups, with no significant difference found between visits. Gastric content volumes were significantly higher for the glucose visit immediately following consumption (P < 0.001) and at 60 minutes (P = 0.007) indicating slower gastric emptying for the glucose compared with the control. In conclusion, following an overnight fast, a low dose oral glucose challenge prevents a reduction in hepatic glycogen content but does not increase it above fasted levels.

Biochemical and histological changes in liver ofNectomys squamipes naturally infected bySchistosoma mansoni

The South American water rat Nectomys squamipes is a wild mammal reservoir of Schistosoma mansoni in Brazil. In the present study, wild rodents were collected in the field and categorized into two groups: infected and uninfected by S. mansoni. Blood was collected to analyze changes in the serum glucose level (mg/dL) and liver fragments were used to determine the hepatic glycogen content (mg of glucose/g tissue). The histological examination showed inflammatory granulomatous lesions in different phases of development in the liver of rodents naturally infected with S. mansoni, in some cases with total or partial occlusion of the vascular lumen. Early lesions were characterized by the presence of inflammatory infiltrate around morphologically intact recently deposited eggs. Despite the significance of these histological lesions, the biochemical changes differed in extent. N. squamipes naturally infected byS. mansoni showed no variation in hepatic glycogen reserves. These findings were accompanied by a significant increase in plasma glucose contents, probably as a consequence of amino acids deamination, which are degraded, resulting in the formation of intermediates used as precursors for the glucose formation, without compromising the reserves of liver glycogen. In the wild, naturally infected N. squamipes can maintainS. mansoni infections without undergoing alterations in its carbohydrate metabolism, which minimizes the deleterious effects of S. mansoni.

Role for leptin in promoting glucose mobilization during acute hyperosmotic stress in teleost fishes

Osmoregulation is critical for survival in all vertebrates, yet the endocrine regulation of this metabolically expensive process is not fully understood. Specifically, the function of leptin in the regulation of energy expenditure in fishes, and among ectotherms, in general, remains unresolved. In this study, we examined the effects of acute salinity transfer (72 h) and the effects of leptin and cortisol on plasma metabolites and hepatic energy reserves in the euryhaline fish, the tilapia (Oreochromis mossambicus). Transfer to 2/3 seawater (23 ppt) significantly increased plasma glucose, amino acid, and lactate levels relative to those in the control fish. Plasma glucose levels were positively correlated with amino acid levels (R2=0.614), but not with lactate levels. The mRNA expression of liver leptin A (lepa), leptin receptor (lepr), and hormone-sensitive and lipoprotein lipases (hsl and lpl) as well as triglyceride content increased during salinity transfer, but plasma free fatty acid and triglyceride levels remained unchanged. Both leptin and cortisol significantly increased plasma glucose levels in vivo, but only leptin decreased liver glycogen levels. Leptin decreased the expression of liver hsl and lpl mRNAs, whereas cortisol significantly increased the expression of these lipases. These findings suggest that hepatic glucose mobilization into the blood following an acute salinity challenge involves both glycogenolysis, induced by leptin, and subsequent gluconeogenesis of free amino acids. This is the first study to report that teleost leptin A has actions that are functionally distinct from those described in mammals acting as a potent hyperglycemic factor during osmotic stress, possibly in synergism with cortisol. These results suggest that the function of leptin may have diverged during the evolution of vertebrates, possibly reflecting differences in metabolic regulation between poikilotherms and homeotherms.

Olanzapine Activates Hepatic Mammalian Target of Rapamycin: New Mechanistic Insight into Metabolic Dysregulation with Atypical Antipsychotic Drugs

Olanzapine (OLZ), an effective treatment of schizophrenia and other disorders, causes weight gain and metabolic syndrome. Most studies to date have focused on the potential effects of OLZ on the central nervous system's mediation of weight; however, peripheral changes in liver or other key metabolic organs may also play a role in the systemic effects of OLZ. Thus, the purpose of this study was to investigate the effects of OLZ on hepatic metabolism in a mouse model of OLZ exposure. Female C57Bl/6J mice were administered OLZ (8 mg/kg per day) or vehicle subcutaneously by osmotic minipumps for 28 days. Liver and plasma were taken at sacrifice for biochemical analyses and for comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry metabolomics analysis. OLZ increased body weight, fat pad mass, and liver-to-body weight ratio without commensurate increase in food consumption, indicating that OLZ altered energy expenditure. Expression and biochemical analyses indicated that OLZ induced anaerobic glycolysis and caused a pseudo-fasted state, which depleted hepatic glycogen reserves. OLZ caused similar effects in cultured HepG2 cells, as determined by Seahorse analysis. Metabolomic analysis indicated that OLZ increased hepatic concentrations of amino acids that can alter metabolism via the mTOR pathway; indeed, hepatic mTOR signaling was robustly increased by OLZ. Interestingly, OLZ concomitantly activated AMP-activated protein kinase (AMPK) signaling. Taken together, these data suggest that disturbances in glucose and lipid metabolism caused by OLZ in liver may be mediated, at least in part, via simultaneous activation of both catabolic (AMPK) and anabolic (mammalian target of rapamycin) pathways, which yields new insight into the metabolic side effects of this drug.

8:24 AM Abstract No. 131 - Transarterial chemoembolization in liver transplant candidates with and without marginal hepatic reserve

Purpose In liver transplant candidates TACE can be used as a bridging treatment until an organ becomes available. However, many of these patients often have hepatic dysfunction. Our purpose is, therefore, to determine the rate of adverse outcomes following TACE in this patient population. Materials and Methods From 2005-2009, 205 consecutive transplant candidates underwent 351 TACE procedures. The procedures were categorized as high-risk if the patients met one of the following criteria: pre-TACE bilirubin >2mg/dl, INR >1.5, creatinine >1.2 mg/dl, platelet count 15, Childs-Pugh class B or C, presence of ascites, or portal venous thrombus. Hepatotoxicity was defined as worsening ascites, encephalopathy, or NCI Common Terminology Criteria for Adverse Events grade 3 or 4 toxicity of bilirubin, AST, ALT, creatinine or INR. The primary outcome was irreversible hepatotoxicity leading to urgent liver transplantation or death within 6 weeks of the procedure. Results Of the 351 TACE procedures, 236 procedures were determined to be high-risk in 133 patients (38-77 years old; 106 males and 27 females) and 115 procedures were determined to be low-risk in 72 patients (38-78 years old; 51 males and 21 females). The high-risk patients developed irreversible hepatotoxicity in 25 of the procedures (10.5%), 7 of which lead to an urgent liver transplant or death (3.0%). In comparison, the low-risk patients developed irreversible hepatotoxicity in 1 procedure (0.9%), none of which lead to an urgent liver transplant or death (0%). Conclusion TACE can be performed safely in liver transplant candidates with baseline hepatic dysfunction. However, poor hepatic reserves increase the risk of irreversible hepatotoxicity, which may require urgent liver transplantation or lead to death. Future work studying specific risk factors may guide the selection of high-risk liver transplant candidates for TACE treatment.

Infusion of CD133+ Bone Marrow–Derived Stem Cells After Selective Portal Vein Embolization Enhances Functional Hepatic Reserves After Extended Right Hepatectomy

This study was designed to evaluate the clinical outcome of patients undergoing portal vein embolization (PVE) and autologous CD133 bone marrow-derived stem cell (CD133+ BMSC) application before extended right hepatectomy. We have previously shown that portal venous infusion of CD133+ BMSCs substantially increases hepatic proliferation, when compared with PVE alone. : Among 40 consecutive patients with a median follow-up of 28 months (7.4-57.2) scheduled for extended right hepatectomy, we compared a preconditioned group with PVE and CD133+ BMSC cotreatment (PVE+SC group, n = 11) and a group pretreated only with PVE (PVE group, n = 11). Functional and overall outcomes after extended right hepatectomy were evaluated. Patients without presurgical treatment served as controls (n = 18). In preconditioned patients, mean hepatic growth of segments II/III 14 days after PVE in the PVE+SC group was significantly higher (138.66 mL ± 66.29) when compared with that of PVE group patients (62.95 mL ± 40.03; P = 0.004). There were no significant differences among all 3 groups regarding general and oncological characteristics and functional parameters on postoperative day (POD) 7. Lack of hepatic preconditioning, extrahepatic extension of resection, and postoperative complications were of negative prognostic value, using univariate analysis (P < 0.05). In multivariate analysis, freedom from postoperative major complications (P = 0.012), coagulation status on POD 7 (international normalized ratio < 1.4; P = 0.027), and presurgical expansion of the future liver remnant volume (P = 0.048) were positively associated with overall survival. Post hoc analysis revealed a better survival for the PVE+SC group (P = 0.028) compared with the PVE group (P = 0.094) and compared with controls. Promising data from this survival analysis suggest that PVE, together with CD133+ BMSC pretreatment, could positively impact overall outcomes after extended right hepatectomy.