Lead inhalation and hepatic damage: Morphological and functional evaluation in mice.

Lead (Pb) is a heavy metal that plays an unknown biological role and is very toxic even at low concentrations. The main sources of Pb are Pb-contaminated areas in industrial areas or landfills. Inhalation is one of the most common routes of exposure to this metal, but there is little information on its effect on the liver. Thirty male mice were exposed to 0.1 M Pb acetate by inhalation for 8 weeks, twice a week for 1h. A recovery group was free of exposure for 4 weeks. Histological evaluation showed an increase in the inflammatory infiltrate and in the percentage of meganuclei in the liver. This was observed since the first week and throughout the whole exposure time. A significant increase in the aspartate aminotransferase concentration was observed in the liver function tests; yet, the alanine aminotransferase concentration did not show significant changes. The 4-hydroxynonenal (4-HNE) and nitrotyrosine levels in Pb-exposed mice, identified by immunohistochemistry, showed a significant increment compared to the controls. This effect was observed throughout Pb exposure. After a 4-week period of suspended exposure, recovery time, the concentration of 4-HNE and nitrotyrosine decreased to similar levels of those previously observed in controls, this suggests a decrease in the generation of oxidative stress by Pb inhalation. Although our results suggest that the lungs are the first contact organs and filters during Pb inhalation, this metal eventually reaches the liver and might cause damage by oxidative stress. This damage can decrease in time if exposure is discontinued.

Preischemic transfusion of old packed RBCs exacerbates early-phase warm hepatic ischemia reperfusion injury in rats.

BACKGROUND: Hepatic innate immune cells are considered to play a central role in the early phase of hepatic ischemia reperfusion (IR) injury. Transfusion of old red blood cells (RBCs) is known to prime immune cells, and transfusion before IR may exacerbate liver injury because of the expected hyperresponsiveness of immune cells. MATERIALS AND METHODS: Twenty-four Sprague-Dawley rats were divided into four groups: sham operation (Sham); hepatic IR only (IR Control); and two transfusion groups, preischemic (Pre-T) and postischemic (Post-T), in which allogeneic RBCs stored for 2 weeks were transfused before hepatic IR or after reperfusion, respectively. Partial hepatic ischemia was induced for 90 min, and reperfusion was allowed for 120 min. Serum alanine transaminase levels, area of necrosis, and apoptotic cells were then assessed. Inflammatory (tumor necrosis factor alpha, interleukin 1 beta [IL-1ß], IL-6, IL-10, and cyclooxygenase 2) and oxidative mediators (heme oxygenase 1, superoxide dismutase, and glutathione peroxidase 1) were assessed for elucidating the relevant mechanisms underlying the hepatic injury. RESULTS: Pre-T, but not Post-T, showed increased serum alanine transaminase levels than IR Control (P < 0.05). Area of necrosis was more severe in Pre-T than in IR Control or Post-T (P < 0.01), and apoptotic cells were also more abundant in Pre-T than in IR Control (P < 0.01). tumor necrosis factor alpha and IL-6 levels were higher in Pre-T than in IR Control or Post-T (P < 0.05), with no significant difference in cytoprotective protein levels. CONCLUSIONS: Preischemic transfusion of old RBCs aggravated hepatic injury. Inflammatory cytokines seemed to play a crucial role in liver injury exacerbation. Our results indicate that transfusion before hepatic ischemia may be detrimental.

Acute liver dysfunction not resulting from hepatitis virus in immunocompetent children.

BACKGROUND: The aim of the present study was to clarify the roles of cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) in immunocompetent children with acute liver dysfunction not resulting from hepatitis virus. METHODS: Sixty-eight children (median age, 3 years) hospitalized as a result of acute liver dysfunction were enrolled in this study. Hepatitis A, B, and C were excluded. The prevalence of CMV, EBV, and HHV-6 and viral DNA load in whole blood was prospectively evaluated on multiplex real-time polymerase chain reaction (PCR). RESULTS: Of the 68 children with acute liver dysfunction, multiplex real-time PCR was positive in 30 (44%). CMV, EBV, and HHV-6 DNA were detected in 13 (19%), 14 (21%), and seven (10%), respectively. Serum CMV immunoglobulin (Ig)G/IgM and EBV viral capsid antigen IgG/IgM were measured in 40 (CMV DNA positive, n = 10; negative, n = 30) and 45 (EBV DNA positive, n = 14; negative, n = 31) of the 68 children, respectively. Eighteen percent (CMV, 7/40) and 9% (EBV, 4/45) were positive for both PCR and viral-specific IgM. There was no significant difference in CMV and EBV viral load between IgM-positive and -negative children with viremia. CONCLUSIONS: CMV, EBV, and HHV-6 DNA were frequently detected in immunocompetent children with acute liver dysfunction, but primary CMV and EBV infection were confirmed in 10-20% of the children with acute liver dysfunction. The combination of PCR assay and serology is necessary to make a diagnosis of acute liver dysfunction due to primary CMV, EBV and/or HHV-6 infection in immunocompetent children.

DIRECTED CYTOKINE THERAPY IN COMPLEX TREATMENT OF PATIENTS WITH OBSTRUCTIVE JAUNDICE OF CHOLELITHIC GENESIS.

The article analyzed the results of surgical treatment of 137 patients with obstructive jaundice of benign genesis. An immune status was studied in serum in dynamics before surgery. The rates of CD3, CD4, CD8, CD19, Ig A, M, G were determined on the first, third, seventh and fourteenth days after operation. The levels of TNFα, IFNγ, IL-2, IL-6, IL-4, IL-10 were investigated in serum and at the same time TNFα, IL-4, IL-6 were noted in the bile duct and IL-6 - in urine. Obstructive jaundice of cholelithiс genesis is characterized by disbalance of immune and cytokine status. The depth of disbalance depends on the degree of hepatic dysfunction and presence of purulent cholangitis. The directed cytokine therapy by ronkoleykin influenced positively on elimination of disbalance in immune and cytokine status and this therapy improved results of surgery in postoperative period.

Differential Effects of Gut-Homing Molecules CC Chemokine Receptor 9 and Integrin-ß7 during Acute Graft-versus-Host Disease of the Liver.

Homing of allogeneic donor T cells to recipient tissue is imperative for the development of acute graft-versus-host disease (GVHD) after bone marrow transplantation (BMT). In this study we show that alteration of T cell homing due to integrin-ß7 deficiency on T cells or its ligand MAdCAM-1 in BMT recipients contributes to the pathophysiology of experimental GVHD. In contrast, lack of CC chemokine receptor 9 on donor T cells alters tissue homing but does not impact GVHD survival. We further demonstrate that MAdCAM-1 is aberrantly expressed in hepatic murine GVHD as well as in patients with active liver GVHD. However, infiltration of donor T cells in gut but not liver was dependent of MAdCAM-1 expression, indicating, that homing and/or retention of donor T cells rests on divergent molecular pathways depending on the GVHD target tissue.

Engraftment Syndrome after Autologous Stem Cell Transplantation: An Update Unifying the Definition and Management Approach.

Engraftment syndrome (ES) encompasses a continuum of periengraftment complications after autologous hematopoietic stem cell transplantation. ES may include noninfectious fever, skin rash, diarrhea, hepatic dysfunction, renal dysfunction, transient encephalopathy, and capillary leak features, such as noncardiogenic pulmonary infiltrates, hypoxia, and weight gain with no alternative etiologic basis other than engraftment. Given its pleiotropic clinical presentation, the transplant field has struggled to clearly define ES and related syndromes. Here, we present a comprehensive review of ES in all documented disease settings. Furthermore, we discuss the proposed risk factors, etiology, and clinical relevance of ES. Finally, our current approach to ES is included along with a proposed treatment algorithm for the management of this complication.

Lack of association between CD40 polymorphisms and acute rejection in German liver transplant recipients.

CD40 and its ligand, CD154, are major costimulatory molecules whose interactions are important in alloreactive transplant rejection. The aim of this study was to examine the association of CD40 polymorphisms with the susceptibility to acute rejection episodes in liver transplantation. In total, 112 liver transplant recipients with biopsy proven acute rejections (BPAR), 97 without BPAR (WBPAR), and 112 healthy control individuals were enrolled in the study. Two single nucleotide polymorphisms (SNPs) of CD40 gene (rs1883832 and rs4810485) were genotyped by polymerase chain reaction-allele specific restriction enzyme analysis (PCR-ASRA). Both SNPs has been tested for a recessive and a dominant model. No significant differences were found in the genotype and allele frequencies of the SNPs rs1883832 and rs4810485 between BPAR liver recipients and WBPAR recipients. Our results do not suggest an important role of tested CD40 SNPs in the susceptibility to acute liver transplant rejection in a Caucasian population.

miR-146a ameliorates liver ischemia/reperfusion injury by suppressing IRAK1 and TRAF6.

A critical role of the Toll-like receptor(TLR) and its downstream molecules, including IL-1 receptor-associated kinase 1(IRAK1) and tumor necrosis factor receptor- associated factor 6(TRAF6), in the pathogenesis of liver ischemia/reperfusion (I/R) injury has been documented. Recently a microRNA, miR-146a, was identified as a potent negative regulator of the TLR signaling pathway. In this study, we investigated the role of miR-146a to attenuate TLR signaling and liver I/R injury in vivo and in vitro. miR-146a was decreased in mice Kupffer cells following hepatic I/R, whereas IRAK1 and TRAF6 increased. Overexpression of miR-146a directly decreased IRAK1 and TRAF6 expression and attenuated the release of proinflammatory cytokines through the inactivation of NF-κB P65 in hypoxia/reoxygenation (H/R)-induced macrophages, RAW264.7 cells. Knockdown experiments demonstrated that IRAK1 and TRAF6 are two potential targets for reducing the release of proinflammatory cytokines. Moreover, co-culture assays indicated that miR-146a decreases the apoptosis of hepatocytes after H/R. In vivo administration of Ago-miR-146a, a stable version of miR-146a in vivo, protected against liver injury in mice after I/R via inactivation of the TLR signaling pathway. We conclude that miR-146a ameliorates liver ischemia/reperfusion injury in vivo and hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6.

Secondary hemophagocytic lymphohistiocytosis (HLH) from a presumed brown recluse spider bite.

Systemic loxoscelism is a rare complication after Loxosceles reclusa (brown recluse spider) envenomation. Loxosceles venom contains pro-inflammatory proteins, which have been shown to be elevated in patients with hemophagocytic lymph histiocytosis. We present a case of a 10-year-old male that developed presumed systemic loxoscelism, secondary hemophagocytic lymphohistiocytosis with hepatic dysfunction and renal failure. He was treated with dexamethasone and made a full recovery.

The paradox of NKp46+ natural killer cells: drivers of severe hepatitis C virus-induced pathology but in-vivo resistance to interferon α treatment.

OBJECTIVE: There is evidence that natural killer (NK) cells help control persistent viral infections including hepatitis C virus (HCV). The phenotype and function of blood and intrahepatic NK cells, in steady state and after interferon (IFN) α treatment has not been fully elucidated. DESIGN: We performed a comparison of NK cells derived from blood and intrahepatic compartments in multiple paired samples from patients with a variety of chronic liver diseases. Furthermore, we obtained serial paired samples from an average of five time points in HCV patients treated with IFNα. RESULTS: Liver NK cells demonstrate a distinct activated phenotype compared to blood manifested as downregulation of the NK cell activation receptors CD16, NKG2D, and NKp30; with increased spontaneous degranulation and IFN production. In contrast, NKp46 expression was not downregulated. Indeed, NKp46-rich NK populations were the most activated, correlating closely with the severity of liver inflammation. Following initiation of IFNα treatment there was a significant increase in the proportion of intrahepatic NK cells at days 1 and 3. NKp46-rich NK populations demonstrated no reserve activation capacity with IFNα treatment and were associated with poor viral control on treatment and treatment failure. CONCLUSIONS: NKp46 marks out pathologically activated NK cells, which may result from a loss of homeostatic control of activating receptor expression in HCV. Paradoxically these pathological NK cells do not appear to be involved in viral control in IFNα-treated individuals and, indeed, predict slower rates of viral clearance.

Nuevos mecanismos en la defensa natural del hígado frente a la lesión / No disponible

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Hemostatic analysis of a 13 year old with antiphospholipid syndrome and restrictive pericarditis.

Antiphospholipid syndrome is an autoimmune thrombophilic disorder that is uncommon in adults and remarkably rare in children. Thrombotic etiological factors are variable in antiphospholipid syndrome, including antibody-antigen complex-mediated platelet activation, inhibition of anticoagulants, or attenuation of fibrinolysis. We present the case of a child with antiphospholipid syndrome presenting with syncope, constrictive pericarditis and hepatic enlargement that was found to have platelet-mediated hypercoagulability and marked clot lysis via thrombelastography in the preoperative period. Restoration of circulation following pericardectomy and inotropic support was associated with attenuation of hypercoagulability and fibrinolysis. It is concluded that the etiological factors responsible for antiphospholipid syndrome-mediated hemostatic abnormalities and the probable effects of hepatic hypoperfusion on clot lysis in this patient were detected with thrombelastography, and similar thrombelastographic analyses are recommended to compliment standard coagulation assessments of patients with antiphospholipid syndrome.

Disfunción hepática en sepsis / Hepatic dysfunction during sepsis

La disfunción hepática en sepsis corresponde a la alteración de la función hepatocelular que se produce en el síndrome de respuesta inflamatoria sistémica (SRIS), se asocia a un mal pronóstico sobre todo cuando se manifiesta en el contexto de falla orgánica múltiple (FOM), y su mortalidad es muy elevada cuando existen más de tres órganos comprometidos. Las manifestaciones clínicas se presentan habitualmente después de la segunda semana de evolución, con elevación discreta de las aminotransferasas, fosfatasas alcalinas y de la gamaglutamiltranspeptidasa, lo más característico es la elevación de la bilirrubina incluso hasta sobre 10 mg/dl lo cual se asocia a un mal pronóstico. Generalmente los valores de protrombina se encuentran conservados, incluso en la etapa tardía de la sepsis. Sin embargo, la disfunción hepática en SRIS se presenta como una alteración global de la función hepática donde la capacidad detoxificadora de toxinas y bacterias está disminuida, y una gran carga de endotoxinas proveniente de la circulación esplácnica perpetúa la cadena inflamatoria que caracteriza al SRIS y a la FOM. No existe una terapia específica para disfunción hepática en sepsis sin embargo son importantes la etapa de reanimación inicial, la terapia antibiótica, también la iniciación precoz de la nutrición enteral para evitar el sobrecrecimiento bacteriano y disminuir la oferta de endotoxinas. Terapias como la proteína C activada recombinante surgen como promisorias, pero deben realizarse estudios controlados para establecer su verdadero lugar como terapia validada en sepsis grave.