Rise In Transaminases Research Articles

Acute Hepatitis: A Rare Complication of Influenza A

Influenza A is principally a respiratory virus; although gastrointestinal involvement occurs, hepatitis is rare and has not been reported in a patient without a systemic febrile illness.Table 1In 12/2014, a 90-year-old man presented to the emergency department with two days of upper respiratory tract symptoms, lethargy, poor oral intake, and acute encephalopathy. In the ED he was afebrile without headache, shortness of breath, or myalgias. Physical examination revealed hypertension, hypoxia (88%), and moderate confusion. Chest and abdomen exams were normal. An Influenza A rapid test was positive. AST and ALT were 2,430 IU/L and 2220 IU/L, respectively. In addition, the INR was 1.43, D-dimer > 20,000 IU/L, LDH 2,190 IU/L, and fibrinogen was 154mg/dL. Diagnoses of acute hepatitis and disseminated intravascular coagulation were made. The patient had been taking amiodarone (6 mos) and simvastatin (2 yrs), which were discontinued. He was medically resuscitated in the Intensive Care Unit. Transaminases returned to near normal at post-admission day 10. Evaluation for common viral causes of acute hepatitis was negative. Consideration was given to drug-induced hepatitis, although both amiodarone and simvastatin had been well tolerated and unassociated with prior transaminase elevation. According to Naranjo's scale for estimating the probability of adverse drug reactions, this patient's presentation was calculated to be 4 out of 13, making amiodarone and/or simvastatin possible causes of hepatic injury. Influenza is not a hepatotropic virus. Although the mechanisms of liver injury in influenza are not fully elucidated, hepatocyte damage has been shown to be mediated by influenza-specific T-cells that interact with Kupffer cells in the absence of influenza antigen in the liver. It has been reported that during infection, influenza-specific T-cells undergo massive expansion in the lung as well as the liver, and the size of the T-cell immune response correlates with the magnitude of the hepatic inflammatory response. In experimental influenza infection in humans, transaminase elevation was not associated with fever. Given the prompt recovery of his transaminase levels and subsequent normal liver ultrasound, we believe that the acute rise in transaminases was the result of Influenza A. While it is possible that the hepatitis was secondary to amiodarone or simvastatin, it is more likely that this was an uncommon presentation for hepatitis secondary to influenza.

Recurrent drug-induced liver injury (DILI) with ciprofloxacin and amoxicillin/clavulanic

Ciprofloxacin and amoxicillin/clavulanic are two widely used antibiotics due to their high efficacy and few side effects. While the percentage of hepatotoxicity of these antibiotics is low, their frequent use has led to a progressive increase in the number of cases. Both antibiotics have been associated with a wide variety of hepatotoxic reactions, from a slight rise of transaminases to fulminant hepatitis. Once hepatotoxicity secondary to a drug appears, the first step is to discontinue the drug. Physicians may opt to administer an alternative treatment with a different chemical structure. It should be borne in mind, however, that different chemical structures may also cause recurrent drug-induced liver injuries (DILI). We present the case of a patient who consecutively developed DILI due to ciprofloxacin and amoxicillin/clavulanic.

Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity.

Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMT(IA)) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. The degree of myelosuppression following HD-MTX was similar for patients with TPMT(IA) and patients with high TPMT activity (TPMT(HA)), when HD-MTX started with same blood counts and 6MP doses. However, since TPMT(IA) had lower blood counts at initiation of HD-MTX compared with TPMT(HA) patients (median WBC 2.8 vs. 3.3 × 10⁹/L, P = 0.01; median ANC 1.4 vs. 1.7 × 10⁹/L, P = 0.02), TPMT(IA) continued to have lower WBC and ANC levels compared with TPMT(HA) during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMT(IA) and TPMT(HA) patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses). For both TPMT(IA) and TPMT(HA) patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.

Mercaptopurine/Methotrexate maintenance therapy of childhood acute lymphoblastic leukemia: clinical facts and fiction.

The antileukemic mechanisms of 6-mercaptopurine (6MP) and methotrexate (MTX) maintenance therapy are poorly understood, but the benefits of several years of myelosuppressive maintenance therapy for acute lymphoblastic leukemia are well proven. Currently, there is no international consensus on drug dosing. Because of significant interindividual and intraindividual variations in drug disposition and pharmacodynamics, vigorous dose adjustments are needed to obtain a target degree of myelosuppression. As the normal white blood cell counts vary by patients' ages and ethnicity, and also within age groups, identical white blood cell levels for 2 patients may not reflect the same treatment intensity. Measurements of intracellular levels of cytotoxic metabolites of 6MP and MTX can identify nonadherent patients, but therapeutic target levels remains to be established. A rise in serum aminotransferase levels during maintenance therapy is common and often related to high levels of methylated 6MP metabolites. However, except for episodes of hypoglycemia, serious liver dysfunction is rare, the risk of permanent liver damage is low, and aminotransferase levels usually normalize within a few weeks after discontinuation of therapy. 6MP and MTX dose increments should lead to either leukopenia or a rise in aminotransferases, and if neither is experienced, poor treatment adherence should be considered. The many genetic polymorphisms that determine 6MP and MTX disposition, efficacy, and toxicity have precluded implementation of pharmacogenomics into treatment, the sole exception being dramatic 6MP dose reductions in patients who are homozygous deficient for thiopurine methyltransferase, the enzyme that methylates 6MP and several of its metabolites. In conclusion, maintenance therapy is as important as the more intensive and toxic earlier treatment phases, and often more challenging. Ongoing research address the applicability of drug metabolite measurements for dose adjustments, extensive host genome profiling to understand diversity in treatment efficacy and toxicity, and alternative thiopurine dosing regimens to improve therapy for the individual patient.

Statin associated hepatic adverse effects: a retrospective review from a regional hospital in sultanate of oman.

This study aimed at evaluating the prevalence, pattern and predisposing factors for hepatic adverse effects with statins in a regional hospital in Sultanate of Oman. A retrospective review of the patient files in Department of Medicine during the year 2011 was done to evaluate any hepatic dysfunction possibly related to statins among the patients. For each case of suspected statin induced hepatic effect, additional details on temporal relationship, pattern of presentation, management, final outcome and any contributing factors were obtained. Difference in the occurrence of hepatic effects based on the patient demographics and drug characteristics was additionally evaluated. A total of 927 patients meeting the inclusion criteria were included for the study. Mean age of the evaluated patients was 63.1 ± 11.37 and median duration of use of statin in months was 22 (IQR, 43.25). In 40 (4%) of the 927 patients, there was presence of a hepatic effect considered to be statin related and only in 12 (1%) patients a significant transaminase rise (>3 times) was observed. Median duration of use of statin among those patients who developed suspected statin induced hepatic effects and those who did not was 45 (IQR,52) and 21 (IQR, 43) months, respectively and the difference observed was statistically significant. A significant difference in the prevalence of hepatic effects was observed only based on the duration of statin use. There was an infrequent occurrence of significant hepatic effects associated with statins in the study population. Our results support the latest recommendations including from United States Federal Drug Administration (US FDA) that statins appear to be associated with a very low risk of serious liver injury and that routine periodic monitoring of transaminases does not appear to detect or prevent serious liver injury in association with statins.

CD8+ T Cell Recognition of Epitopes Within the Capsid of Adeno-associated Virus 8–based Gene Transfer Vectors Depends on Vectors’ Genome

Self-complementary adeno-associated viral (AAV) vectors expressing human factor IX (hF.IX) have achieved transient or sustained correction of hemophilia B in human volunteers. High doses of AAV2 or AAV8 vectors delivered to the liver caused in several patients an increase in transaminases accompanied by a rise in AAV capsid-specific T cells and a decrease in circulating hF.IX levels suggesting immune-mediated destruction of vector-transduced cells. Kinetics of these adverse events differed in patients receiving AAV2 or AAV8 vectors causing rise in transaminases at 3 versus 8 weeks after vector injection, respectively. To test if CD8+ T cells to AAV8 vectors, which are similar to AAV2 vectors are fully-gutted vectors and thereby fail to encode structural viral proteins, could cause damage at this late time point, we tested in a series of mouse studies how long major histocompatibility (MHC) class I epitopes within AAV8 capsid can be presented to CD8+ T cells. Our results clearly show that depending on the vectors' genome, CD8+ T cells can detect such epitopes on AAV8's capsid for up to 6 months indicating that the capsid of AAV8 degrades slowly in mice.

Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management.

Abnormalities in liver function tests, including transient and self-limiting hypertransaminasemia, cholestatic disease and hepatitis, can develop during treatment with anti-tumour-necrosis-factor (TNF) therapy. The optimal management of liver injury related to anti-TNF therapy is still a matter of debate. Although some authors recommend discontinuing treatment in case of both a rise of alanine aminotransferase more than 5 times the upper limit of normal, or the occurrence of jaundice, there are no standard guidelines for the management of anti-TNF-related liver injury. Bibliographical searches were performed in PubMed, using the following key words: inflammatory bowel disease (IBD); TNF inhibitors; hypertransaminasemia; drug-related liver injury; infliximab. According to published data, elevation of transaminases in patients with IBD treated with anti-TNF is a common finding, but resolution appears to be the usual outcome. Anti-TNF agents seem to be safe with a low risk of causing severe drug-related liver injury. According to our centre experience, we found that hypertransaminasemia was a common, mainly self-limiting finding in our IBD cohort and was not correlated to infliximab treatment on both univariate and multivariate analyses. An algorithm for the management of liver impairment occurring during anti-TNF treatment is also proposed and this highlights the need of a multidisciplinary approach and suggests liver biopsy as a key-point in the management decision in case of severe rise of transaminases. However, hepatic injury is generally self-limiting and drug withdrawal seems to be an exception.

Early allograft dysfunction: Causes, recognition, and management

Early allograft dysfunction: Causes, recognition, and management

PWE-130 Effect Of N Acetylcysteine (NAC) in Hypoxia Induced Liver Injury (HILI)–A Randomized Placebo Control Clinical Trial

IntroductionHILI is common with a prevalence of 10% in US. Transient shift of intra hepatic hemodynamic compromise leads to tissue hypoxia and induces hypoxia induced protein (HIP), heat shock protein...

Hepatobiliary Quiz-6 (2013)

1.Regarding anti-tubercular therapy (ATT) related hepatotoxicity the following are TRUE:1.Transient asymptomatic rise of transaminases is common and settles spontaneously with continuation of isoniazid.2.Most common pattern of ATT induced hepatotoxicity is cholestatic.3.ATT induced acute liver failure has worse prognosis virus related acute liver failure.4.Combination therapy increases the risk of hepatotoxicity.5.Daily dosing regimen increases risk of hepatotoxicity.2.Regarding the mechanisms of ATT related hepatotoxicity the following are TRUE:1.Slow acetylators have less risk of isoniazid induced hepatotoxicity.2.Rifampicin increases isoniazid induced hepatotoxicity by inducing cytochrome P450 enzymes.3.Rifampicin can cause both conjugated and unconjugated hyperbilirubinemia without hepatocellular damage.4.Pyrazinamide induced hepatotoxicity is dose dependent.5.Women have lower risk of ATT induced hepatotoxicity due to lower cytochrome P450 enzyme activity.3.Regarding model for end stage liver disease (MELD) the following are TRUE EXCEPT:1.MELD was initially developed as a score to predict survival following surgical porto-systemic shunting for refractory ascites or variceal bleeding.2.Upper value of serum creatinine is capped at 4 mg/dl.3.Addition of etiology of liver disease improves the predictive ability of the MELD score.4.MELD scores are also predictive of post transplant morbidity, length of ICU stay and cost of transplantation.5.Addition of other recipient and donor criteria to MELD may be useful in optimizing transplant risk in patients with high MELD scores.4.Regarding use of MELD for applications other than liver transplantation the following are TRUE EXCEPT:1.MELD score does not predict occurrence of infection and mortality in hospitalized patients with cirrhosis.2.MELD score can be used to estimate mortality after surgery in patients with cirrhosis.3.MELD score can be used to estimate hepatic failure after hepatic resection for hepatocellular carcinoma.4.MELD score does not predict mortality after hepatic resection for hepatocellular carcinoma.5.MELD is a predictor of rebleeding and mortality after variceal hemorrhage.5.Regarding development of non-alcoholic fatty liver disease (NAFLD) after liver transplant the following are TRUE:1.Recurrence of NAFLD in patients transplanted for cryptogenic cirrhosis is almost universal.2.De-novo development of NAFLD in patients transplanted for other indications is rare.3.NAFLD post liver transplant is an insidious process requiring months to years to develop.4.Risk factors for recurrent or de-novo NAFLD after transplant are similar to those for NAFLD in native liver.5.Well defined evidence based paradigms are available for treatment of NAFLD after liver transplant.6.Regarding hepatitis C virus (HCV) infection in patients of end stage renal disease (ESRD) on regular hemodialysis the following are TRUE:1.The prevalence of HCV infection is higher in ESRD patients than in the general population.2.Duration of hemodialysis is not a risk factor for HCV positivity.3.Guidelines routinely recommend use dedicated dialysis machines, patient isolation, and a ban on reuse of dialyzer in patients with HCV infection.4.Routine screening for HCV infection should be done in all ESRD patients on hemodialysis.5.HCV positive patients have worse outcome after renal transplant.7.Regarding gastric varices in patients with portal hypertension the following are TRUE EXCEPT:1.Gastric varices account for only 5–10% of all upper digestive bleeds.2.Bleeding from gastric varices is correlated with hepatic venous pressure gradient.3.Patients with extrahepatic portal vein obstruction are more likely to have isolated gastric varices than patients with cirrhosis.4.Transjugular intrahepatic porto-systemic shunt is the first line treatment of gastric varices.5.Balloon occluded retrograde transvenous obliteration is a newer modality for treatment of gastric varices.8.Regarding the mechanisms responsible for progression of steatosis to steatohepatitis in NAFLD the following are TRUE EXCEPT:1.Hepatic triglyceride is directly toxic to the liver and degree of steatosis is correlated with inflammation.2.Free fatty acids cause liver injury directly as well as via lipid peroxidation.3.Patients with steatohepatitis have higher oxidative stress compared with chronic viral hepatitis.4.Levels of inflammatory cytokines are similar in steatohepatitis and simple steatosis.5.Iron overload and hemochromatosis gene mutations are important cause of oxidative stress in Asian patients with steatohepatitis.9.Regarding primary cholestatic liver diseases the following are TRUE:1.Specific anti-nuclear antibodies directed against nuclear body or envelope proteins are useful for diagnosis of primary biliary cirrhosis (PBC).2.The Barcelona and Paris criteria are used to asses response to therapy in primary sclerosing cholangitis (PSC).3.Ursodeoxycholic acid decreases risk of colonic neoplasia in PSC.4.Colectomy prior to liver transplantation decreases risk of recurrence of PSC after transplantation.5.Immunoglobulin G4-associated cholangitis is steroid unresponsive.10.Regarding evaluation of a patient with ascites the following are TRUE EXCEPT:1.Bedside inoculation of ascitic fluid into blood culture bottles increases bacterial detection.2.Yield of malignant cytology improves if multiple samples of fluid are tested.3.CA 125 is a useful investigation in a patient with suspected malignant ascites.4.Serum-ascites albumin gradient (SAAG) ≥ 1.1 is has good accuracy for underlying portal hypertensive ascites even in cases of mixed ascites.5.Pro-brain natriuretic peptide cannot differentiate ascites due to heart failure from ascites due to cirrhosis.

Mo1033 Effect of N Acetylcysteine (NAC) in Hypoxia Induced Liver Injury (HILI) - A Randomized Placebo Control Clinical Trial

Introduction HILI is common with a prevalence of 10% in US. Transient shift of intra hepatic hemodynamic compromise leads to tissue hypoxia and induces hypoxia induced protein (HIP), heat shock protein 70 (HSP24.70), Endothelial reticular stress (ER) leading to reperfusion injury (RI). Dramatic rise of transaminases, drastic reversal with restoration of perfusion in weeks follows. In cirrhotics HILI requires liver transplantation. This study evaluated spontaneous recovery and salvage in HILI utilising NAC. Methods Sixty patients (n = 60) with mean arterial pressure (MAP) Exclusions: Organ transplant, Septic shock, Hemodialysis, cancer, acute myocardial Infarct, Tylenol injury, acute viral hepatitis and organ trauma. Results Placebo groups A1, B1: Normalized A1-[LFTs- on 3rd day-(7%), 6th day-(21%), 9th day-(36%) and 12th day-(21%). 1/14(7%) died]. B1(CLD)[ LFTs 3rd day-(19%) 6th (44%) 9 th (25%),2/16(6%) died of sepsis] NAC Groups A2[normalised LFTs 3rd (57%)6th day-(43%) 9 th day (25%), (7%)-one died ] B2 (CLD)[Normalized LFTs- 3rd day-(63%), 6th day-(25%) 9 th1/16(6%), one died] Conclusion This Study postulates that IV NAC (A2, B2) has efficient spontaneous recovery and salvage in non-CLD sub group B2 (63%) > A2(57%) in day 3, in CLD NAC (A2) > placebo (A1) clinical recovery over placebo at 3rd day, (44%) over (36%) - 6th day. Larger trial need to establish the routine usage of IV NAC in HILI. Disclosure of Interest None Declared.

Comparative study of liver functional characteristics in combined pathologies by the method of electron paramagnetic resonance

S 21 ANNUAL CONFERENCE—2013 M isella n eo u s administered intraperitoneally to the animals (group-1) at the dose of 20 mg/kg at 24 h before tumor illumination, and administered intravenously at 5 mg/kg in group-2 animals. The cavity was then illuminated with a flat-cut fiber optic cable through a small incision and the peritoneum is filled with normal saline. Whole-peritoneum was irradiated using a 630-nm CW diode laser with a dose of 100 J/ cm2. The pathologic status was investigated 4 days later. Total tumor count was detected. Results: PDT in group A and B mice resulted in a significant lowered tumor weight and account of tumor nodes compared with the control group. Percentage of cancer necrosis in group A animal significantly higher than in group B and control group. Significant increases in TUNEL-positive cells and Ki-67-positive cells ware seen, indicating that PDT led to not only cell death but also inhibition of cancer proliferation. Conclusions: Preliminary results demonstrate feasibility of PDT for peritoneal carcinomatosis. The results show that PDT is effective for treatment of cholangiocarcinoma, and it will be a novel potential application of laparoscope. Corresponding author: Kai-Wen Huang. E-mail: skywing@ntuh.gov.tw EFFECT OF N ACETYLCYSTEINE (NAC) IN HYPOXIA INDUCED LIVER INJURY (HILI)– A RANDOMIZED PLACEBO CONTROL CLINICAL TRIAL P. Basu, K. Mittimanj, Niraj J. Shah, R. Siriki, K. Rahaman, Niraj Atluri, R. Jr Brown Columbia School of Physicians and Surgeons, Forest Hills Hospital, Hofstra North Shore-LIJ School of Medicine, Forest Hills Hospital, Hofstra North Shore-LIJ School of Medicine, James J Peters VA Medical Center, Mount Sinai School of Medicine, New York Objectives: HILI is common with a prevalence of 10% in US. Transient shift of intra hepatic hemodynamic compromise leads to tissue hypoxia and induces hypoxia induced protein (HIP), heat shock protein 70 (HSP24, 70), Endothelial reticular stress (ER) leading to reperfusion injury (RI). Dramatic rise of transaminases, drastic reversal with restoration of perfusion in weeks follows. In cirrhotics HILI requires liver transplantation. This study evaluated spontaneous recovery and salvage in HILI utilizing NAC. Methods: Sixty patients (n=60) with mean arterial pressure (MAP) A2 (57%) in day 3, in CLD NAC (A2)> placebo (A1) clinical recovery over placebo at 3rd day, (44%) over (36%) 6th day. Larger trial need to establish the routine usage of IV NAC in HILI. Corresponding author: Patrick Basu. E-mail: basu.patrick@gmail.com DIABETES: ITS IMPACT ON LIVER DISEASES Mrudul Vishanji Dharod Deepak Narayan Amarapurkar Bombay Hospital and Medical Research Centre, 12, Marine Lines,

Effect of n acetylcysteine (NAC) in hypoxia induced liver injury (HILI)–a randomized placebo control clinical trial

Objectives: HILI is common with a prevalence of 10% in US. Transient shift of intra hepatic hemodynamic compromise leads to tissue hypoxia and induces hypoxia induced protein (HIP), heat shock protein 70 (HSP24, 70), Endothelial reticular stress (ER) leading to reperfusion injury (RI). Dramatic rise of transaminases, drastic reversal with restoration of perfusion in weeks follows. In cirrhotics HILI requires liver transplantation. This study evaluated spontaneous recovery and salvage in HILI utilizing NAC. Methods: Sixty patients (n=60) with mean arterial pressure (MAP) < 35% and normal LFTs at baseline. Group A (n=28) chronic liver disease (CLD)[ alcohol-11/28(39%), NASH-9/28(32%), Hepatitis C-4/28(14%), hepatitis B-2/28(7%), PBC-1/28 (3%), AIH-1/28(3%). Group B (n=32) [respiratory failure-12/32(37%), CHF-8/32(25%), CVA-2/32(6%), sepsis-6/32(19%), post op-4/32(12%)]. Randomized into Placebo group- A1 (14) & B1 (16) and IV NAC for 48 hours - A2 (14) & B2 (16). Serum Transaminases, Bilirubin, INR, Creatinine and MELD score at 0, 3rd, 6th, 9th and 12th days with MAP and modified Sequential Organ Failure Assessment (SOFA) Score. All patients were allowed standard of care (SOC) and resuscitations if needed. Exclusions: Organ transplant, Septic shock, Hemodialysis, cancer, acute myocardial Infarct, Tylenol injury, acute viral hepatitis and organ trauma. Results: Placebo groups A1, B1: Normalized A1-[LFTs- on 3rd day-(7%), 6th day-(21%), 9th day-(36%) and 12th day-(21%). 1/14(7%) died]. B1(CLD)[ LFTs 3rd day-(19%) 6th (44%) 9 th(25%),2/16(6%) died of sepsis] NAC Groups A2[normalized LFTs 3rd (57%)6th day-(43%) 9 th day (25%), (7%)-one died ] B2 (CLD)[Normalized LFTs- 3rd day-(63%), 6th day-(25%) 9 th1/16(6%), one died]. Conclusion: This Study postulates that IV NAC (A2, B2) has efficient spontaneous recovery and salvage in non-CLD sub group B2 (63%)>A2 (57%) in day 3, in CLD NAC (A2)> placebo (A1) clinical recovery over placebo at 3rd day, (44%) over (36%) - 6th day. Larger trial need to establish the routine usage of IV NAC in HILI.

Heat Shock Protein -70 (HSP- 70) A Novel Surrogate Marker for Hypoxia Induced Liver Injury (HILI): A Prospective Open Label Control Clinical Pilot Study

Purpose: Hypoxic hepatopathy (HH) is a common entity in hospital with impaired hepatic perfusion secondary to transient altered cardio pulmonary hemodynamics, manifesting with sharp rise of transaminases with perfusion injury rarely requiring transplantation. Transaminases are non-specific index of reperfusion injury (IR). HSP are reperfusion signal proteins represent sheer-stress. HSP -70 is one of specific signals of IR impacts on specific target. This study evaluates the utility of a novel marker of HILI. Methods: Sixty (n=60) patients were recruited from Hospital. Group A control (n=20) Group B (n=20) HILI, Group C (n=20) Acute Hepatitis [(Tylenol 8/20 (40%), Acute hepatitis B8/20 (40%) herpes simplex 1/20 (5%) EBV 1/20 (5%) acute hepatitis A 1/20 (5%) unknown 1/20 (5%). All groups underwent serial blood levels of HSP70, Liver and renal functions, MELD score, SOFA score, from day 0, 4,7 and 10. Exclusion; Cardio respiratory failure, renal failure, acute alcoholic hepatitis, sepsis, organ transplant hemolytic syndromes, CVA, MELD > 20, MAP< 90. Results: Group A; HSP 70 was normal. Group B was intermediate on day 0 and very high on day 4, 7 and reverting back to lower levels on day 10. Group C had a low level (mildly elevated) of HSP-70 on all days with the exception of the Tylenol group where it was intermediate levels. View Table - Results.Table: [332] ResultsConclusion: HSP -70 is a relevant surrogate marker for hypoxia induced hepatopathy. HSP-70 levels strongly correlated with HILI and poorly with Tylenol induced liver injury. But negatively with other non-vascular liver injuries. Larger study needed to validate this finding.

Non-alcoholic Fatty Liver Disease: East Versus West

Non-alcoholic fatty liver disease (NAFLD) is an important cause of liver disease worldwide with prevalence ranging from 10% to 30% in various countries. It has become an important cause of unexplained rise in transaminases, cryptogenic cirrhosis, and cryptogenic hepatocellular carcinoma. Pathogenesis is related to obesity, insulin resistance, oxidative stress, lipotoxicity, and resultant inflammation in the liver progressing to fibrosis. Pharmacological treatment in patients with NAFLD is still evolving and the treatment of these patients rests upon lifestyle modification with diet and exercise being the cornerstones of therapy. While there are many similarities between patients with NAFLD from Asia and the West, there are certain features which make the patients with NAFLD from Asia stand apart. This review highlights the data on NAFLD from Asia comparing it with the data from the West.

PWE-269 Heat shock protein-70 (hsp-70) a novel surrogate marker for hypoxia induced liver injury (HILI)—a prospective open level control clinical pilot study

IntroductionHypoxic hepatopathy (HH) is a common entity in hospital with impaired hepatic perfusion secondary to transient altered cardio pulmonary haemodynamics, manifesting with sharp rise of transaminases with perfusion injury rarely...

A phase I study of the CDK inhibitor dinaciclib (SCH 727965) administered every 3 weeks in patients (pts) with advanced malignancies: Final results.

3080 Background: Dinaciclib is a potent and selective inhibitor of CDKs 1, 2, 5, and 9 with anti-tumor activity in multiple tumor cell lines and xenograft models. Methods: Dinaciclib is administered every 3 weeks in pts with advanced malignancies. Part 1: accelerated titration design to establish the RP2D of a 2-hr IV infusion. Part 2: 8 and 24-hr continuous IV infusions. Part 3: determined effect of the CYP3A4 inhibitor aprepitant on PK. PD assessments: ex vivo lymphocyte proliferation assay; FDG-PET/CT scans; and skin and/or tumor biopsies for IHC of cdk targets. Results: 81 pts treated. Part 1: Doses 1.85 to 58 mg/m2. RP2D 50 mg/m2. DLTs: non-neutropenic sepsis (1), neutropenic fever (2), neutropenia with pneumonia (1), hypotension (1), and rise in transaminases (3). Part 2: 7.4 and 10.4 mg/m2 well tolerated as 8- and 24-hr infusions, respectively. DLTs seen at lower doses with 8-hr and 24-hr vs 2-hr infusions. 8-hr DLTs: neutropenia with or without fever (5), hypotension (1), syncope (1), and elevated transaminases (2). 24-hr DLTs: rise in bilirubin (1) and delirium (1). Part 3: pts received dinaciclib 29.6 mg/m2 by 2-hr infusion +/- aprepitant. Among all pts, the most common treatment-related adverse events were nausea, vomiting, diarrhea, neutropenia, and fatigue. Dinaciclib was rapidly eliminated with a t1/2 of 1.4-3.3 hrs. Coadministration of aprepitant had no significant effect on PK. PD: Dose and infusion time correlated with degree and durability of suppression of lymphocyte proliferation. Tumor metabolic changes occurred in some pts by FDG-PET at day 8 but were not predictive of response. No objective responses by RECIST; SD ≥6 cycles (range 6-30) achieved in 10 pts. Pre/post tumor biopsies from 2 pts with melanoma show reduced phospho-Rb [pT356] post-treatment; total Rb was preserved. In 1 pt, p27 and p53 increased post-treatment, consistent with cdk2 and cdk9 inhibition. Analysis of skin biopsies ongoing. Conclusions: Dinaciclib has an acceptable safety profile at 50, 7.4 and 10.4 mg/m2 for 2-, 8- and 24-hr infusions, respectively, without PK interaction with aprepitant. Prolonged SD was achieved in some pts. Trials are ongoing in hematologic malignancies and melanoma.

Oseltamivir treatment and prophylaxis in a neonatal intensive care unit during a 2009 H1N1 influenza outbreak

To evaluate safety of oseltamivir in neonates with significant comorbidities in a level-III neonatal intensive care unit during an outbreak of 2009 H1N1 influenza. We performed a retrospective chart review of neonates who received oseltamivir for treatment and prophylaxis of influenza during the outbreak. A total of 11 neonates received twice daily dosing and 21 neonates received once daily dosing (12 to 25 mg per dose) for treatment and prophylaxis of influenza, respectively. Age ranged from 2 days to 11.4 months (mean, 2.1 months). Corrected gestational age and weight at initiation of oseltamivir ranged from 32 to 86 weeks (mean, 41 weeks) and 775 to 8635 g (mean, 3074 g), respectively. All had complex underlying conditions. Oseltamivir was well tolerated. Neurologic adverse effects or mortality attributable to oseltamivir were not identified. Mild rash and gastrointestinal signs in four infants resolved without oseltamivir discontinuation. Three showed a transient rise in transaminases; all returned to baseline after completing therapy. Oseltamivir appears to be well tolerated in preterm and term neonates and infants with complex underlying conditions. More studies are needed to determine optimal dosing for treatment and prophylaxis in this vulnerable age group.

Uncoupling Protein-2 Deficient Mice Are Not Protected Against Warm Ischemia/Reperfusion Injury of the Liver

Uncoupling protein-2 (UCP2) might play an important role in mediating ischemia/reperfusion (I/R) injury due to its function in uncoupling of oxidative phosphorylation and in the proton leak-associated increase of reactive oxygen species (ROS) production. The aim of this study was to elucidate the role of UCP2 in hepatic I/R injury. UCP2 wild type and UCP2 deficient mice were subjected to I/R of the left liver lobe. Sham-operated animals without I/R served as controls. Intravital fluorescence microscopy was used for assessing postischemic microcirculatory dysfunction. Indicators of hepatic inflammatory response, oxidative stress, and bioenergetic status as well as histomorphology were investigated. Under sham conditions UCP2-/-mice presented slightly but not significantly higher levels of hepatic ATP and energy charge than wild type mice. In addition, they exhibited higher systemic IL-6 levels and intrahepatic leukocyte adherence. After exposure to I/R, the extent of reperfusion injury did not differ between UCP2+/+ and UCP2-/-mice, as indicated by a comparable loss of sinusoidal perfusion, hepatic ATP, and energy charge levels, as well as rise of transaminases and disintegration of liver structures. Intrahepatic leukocyte adherence and plasma IL-6 levels of postischemic UCP2-/-mice still exceeded those of UCP2+/+mice. UCP2 appears to be of minor relevance for the manifestation and extent of postischemic reperfusion injury in nondiseased livers with the increased ATP availability being counteracted by the higher pro-inflammatory IL-6 levels in UCP2 deficient mice.

Insulin resistance induced by high-fructose diet potentiates carbon tetrachloride hepatotoxicity

Insulin resistance (IR) is recognized as a contributory factor for a variety of liver diseases. The present study investigates the susceptibility of liver to the toxic actions of carbon tetrachloride (CCl(4)) in a rat model of IR, induced by feeding a high-fructose diet (60 g/100 g) for 30 days. A sub-lethal dose of CCl(4) (2 mL/kg intraperitoneally [i.p.], in corn oil) was administered and the outcome of hepatotoxicity was assessed at 0 hour and at 6, 12, 24 and 36 hours after CCl(4) administration. After 30 days of fructose feeding, the rats showed IR, decline in liver antioxidant status and rise in lipid peroxidation. Liver dysfunction in fructose-fed rats was evident from a rise in transaminases, total bilirubin and a decrease in albumin/globulin ratio in plasma and decreases in nitrite, arginase and increase in protein carbonyl and nitrosothiol content in liver. Increased staining for 3-nitro tyrosine (3-NT) antibody was observed in fructose-fed rat liver as compared to control. CCl(4) (2 mL/kg) caused 100% mortality in fructose-fed rats within 48 hours, while no death of animals occurred in control. CCl(4) caused liver damage in both control and fructose-fed rats. Time-based studies showed that progressive liver injury occurred only in fructose-fed rats from 0, 6, 12, 24 hours, with a peak at 36 hours. In control diet-fed rats, the extent of damage was maximum at 24 hours, which declined at 36 hours. Thus, the toxic effects of CCl(4) are potentiated due to compromised liver function in the setting of IR.