ABSTRACT
OBJECTIVES: To correlate human herpesvirus 6 (HHV-6) viral load with pathologic features in graft acute hepatitis of unknown origin. METHODS: Liver frozen samples from 26 patients with graft hepatitis of unknown origin were available for HHV-6 DNA quantification. RESULTS: In 10 (38.5%) of 26 liver samples, HHV-6 DNA was detectable, with a median viral load of 3.84 log10 copies/106 cells. Confluent periportal necrosis was observed in 4 of 10 patients and associated with high viral load. These 4 patients responded to antiviral therapy. Mild unspecific hepatitis was observed in 4 patients with low intragraft viral load and in 2 patients with high viral load in a context of deep immunosuppression. Patients with HHV-6-negative graft hepatitis disclosed lobular necrotico-inflammatory activity without periportal necrosis. CONCLUSIONS: Our study provides data supporting the pathogenic role of HHV-6 for liver allografts. The presence of confluent periportal necrosis could be a clue for prompt diagnosis of HHV-6-induced graft hepatitis.
Subject(s)
Hepatitis/pathology , Herpesvirus 6, Human/isolation & purification , Liver Transplantation/pathology , Liver/pathology , Roseolovirus Infections/pathology , Adolescent , Adult , DNA, Viral , Female , Hepatitis/virology , Humans , Liver/virology , Male , Middle Aged , Roseolovirus Infections/virology , Viral LoadABSTRACT
Biliary epithelial cells (BEC) are important targets in some liver diseases, including acute allograft rejection. Although some injured BEC die, many can survive in function compromised states of senescence or phenotypic de-differentiation. This study was performed to examine changes in the phenotype of BEC during acute liver allograft rejection and the mechanism driving these changes. Liver allograft sections showed a positive correlation (p < 0.0013) between increasing T cell mediated acute rejection and the number of BEC expressing the senescence marker p21(WAF1/Cip) or the mesenchymal marker S100A4. This was modeled in vitro by examination of primary or immortalized BEC after acute oxidative stress. During the first 48 h, the expression of p21(WAF1/Cip) was increased transiently before returning to baseline. After this time BEC showed increased expression of mesenchymal proteins with a decrease in epithelial markers. Analysis of TGF-ß expression at mRNA and protein levels also showed a rapid increase in TGF-ß2 (p < 0.006) following oxidative stress. The epithelial de-differentiation observed in vitro was abrogated by pharmacological blockade of the ALK-5 component of the TGF-ß receptor. These data suggest that stress induced production of TGF-ß2 by BEC can modify liver allograft function by enhancing the de-differentiation of local epithelial cells.
Subject(s)
Bile Ducts, Intrahepatic/pathology , Cellular Senescence , Epithelial Cells/pathology , Graft Rejection/pathology , Liver Transplantation/pathology , Acute Disease , Bile Ducts, Intrahepatic/metabolism , Biopsy , Blotting, Western , Cells, Cultured , Densitometry , Enzyme-Linked Immunosorbent Assay , Epithelial Cells/metabolism , Gene Expression Regulation , Graft Rejection/genetics , Graft Rejection/metabolism , Humans , Immunohistochemistry , Oxidative Stress/genetics , RNA/genetics , Real-Time Polymerase Chain Reaction , Transforming Growth Factor beta2/biosynthesis , Transforming Growth Factor beta2/genetics , Transplantation, HomologousSubject(s)
Bile Duct Diseases/diagnosis , Bile Duct Diseases/etiology , Biliary Fistula/diagnosis , Biliary Fistula/etiology , Jejunum/diagnostic imaging , Jejunum/pathology , Liver Transplantation/adverse effects , Cholangiography/methods , Cholangiopancreatography, Magnetic Resonance/methods , Diagnosis, Differential , Female , Humans , Infant , Liver Transplantation/diagnostic imaging , Liver Transplantation/pathologyABSTRACT
BACKGROUND: In organ transplant field, although viewed traditionally as instigators of organ allograft rejection, donor-derived interstitial dendritic cells (DCs), including those resident in liver, or host DCs have also been implicated in transplant tolerance in experimental models. This functional dichotomy of DC is governed by various factors, the most important of which appears to be their stage of maturation. This study was designed to examine the effect of zinc finger protein A20 on maturation of DCs resident in rat liver allograft. MATERIALS AND METHODS: Allogeneic (Dark Agouti [DA] rat to Lewis rat) liver transplantation was performed. Adenovirus carrying the full length of A20 was introduced into liver allografts by ex vivo perfusion via the portal vein during preservation (group A20), physiological saline (group PS), and empty Ad vector rAdEasy (group rAdEasy) that served as controls. Acute liver allograft rejection was assessed, and DCs resident in liver allografts were isolated on day 7 after transplantation. Nuclear factor kappa B (NF-κB)-binding activities, surface expression of costimulatory molecules (CD40, CD80, and CD86), expression of interleukin (IL) 12 messenger RNA (mRNA), and allocostimulatory capacity of DCs were measured with electrophoretic mobility shift assay, flow cytometry, reverse transcription-polymerase chain reaction, and mixed lymphocyte reaction (MLR), respectively. RESULTS: Ex vivo transfer of A20 adenovirus by portal vein infusion resulted in overexpression of A20 protein in liver allograft after transplantation. On day 7 after transplantation, histologic examination revealed a mild rejection in group A20 but a more severe rejection in group PS and group rAdEasy. DCs from group A20 liver allografts exhibited features of immature DC with detectable but very low level of NF-κB activity, IL-12 mRNA expression, and surface expression of costimulatory molecules (CD40, CD80, and CD86), whereas DCs from group rAdEasy and group PS liver allograft displayed features of mature DC with high level of NF-κB activity, IL-12 mRNA expression, and surface expression of costimulatory molecules (CD40, CD80, and CD86). DCs from group PS and group rAdEasy liver allograft were potent inducers of DNA synthesis and interferon γ production in MLR, and DCs from group A20 liver allografts induced only minimal levels of cell proliferation and interferon γ production in MLR. CONCLUSIONS: These data suggest that A20 overexpression could effectively inhibit maturation of DCs resident in liver allograft and consequently suppress acute liver allograft rejection.
Subject(s)
Cell Differentiation/physiology , DNA-Binding Proteins/physiology , Dendritic Cells/physiology , Liver Transplantation/pathology , Liver/pathology , Adenoviridae/genetics , Animals , DNA-Binding Proteins/genetics , Dendritic Cells/pathology , Interferon-gamma/metabolism , Interleukin-12/metabolism , Liver/metabolism , Liver/surgery , Male , Models, Animal , NF-kappa B/metabolism , Rats , Rats, Inbred Lew , Rats, Inbred Strains , Transplantation, Homologous , Tumor Necrosis Factor alpha-Induced Protein 3ABSTRACT
BACKGROUND: Mesenchymal stem cell (MSC) therapy can prevent parenchymal cell loss and promotes tissue repair through the action of trophic, secreted molecules. In this study, we investigated whether MSC-conditioned medium (MSC-CM) could protect hepatocytes and sinusoidal endothelial cells (SECs) and stimulate their regeneration in 50% reduced-size liver transplantation (RSLT). MATERIALS AND METHODS: Rats were randomly divided into three groups: sham-operated group, MSC-CM group (rats with 50% RSLT receiving MSC-CM infusion), and medium group (rats with 50% RSLT receiving medium therapy). Graft function, proinflammatory cytokines, incidence of apoptosis, proliferation of hepatocytes and SECs, and the expression of vascular endothelial growth factor and matrix metallopeptidase 9 were assessed in this study. RESULTS: Systemic infusion of MSC-CM prevented the release of liver injury biomarkers and provided a significant survival benefit. Furthermore, MSC-CM therapy resulted in reduction of apoptosis of hepatocytes and SECs. The number of proliferating hepatocytes and SECs increased 1.2- and 1.6-fold, respectively, accompanied by a decrease in the expression levels of several proinflammatory cytokines and a noticeable decrease in infiltration of neutrophils and activation of Kupffer cells. Also, increased expression of vascular endothelial growth factor and matrix metallopeptidase 9 in the grafts was observed after MSC-CM therapy. CONCLUSIONS: These data suggest that MSC-CM therapy in RSLT provides trophic support to the injured liver by inhibiting SEC and hepatocellular death and stimulating their regeneration.
Subject(s)
Culture Media, Conditioned/pharmacology , Liver Regeneration/drug effects , Liver Transplantation/pathology , Liver/injuries , Liver/pathology , Mesenchymal Stem Cells/physiology , Animals , Apoptosis/drug effects , Cell Proliferation/drug effects , Endothelial Cells/drug effects , Endothelial Cells/pathology , Hepatocytes/drug effects , Hepatocytes/pathology , Liver/metabolism , Liver Regeneration/physiology , Male , Matrix Metalloproteinase 9/metabolism , Models, Animal , Rats , Rats, Sprague-Dawley , Vascular Endothelial Growth Factor A/metabolismABSTRACT
CONTEXT: As demand for organs to treat end-stage liver disease increases, donor livers once deemed only marginally suitable for donation are being considered for transplantation. Pathologists are increasingly being asked to evaluate these livers for acceptability. This article provides guidelines for frozen section evaluation of livers for transplantation. OBJECTIVE: This article concentrates on the histopathologic features of transplant suitability with appropriate clinicopathologic correlation for the practicing pathologist. Recommendations for proper handling and sampling of tissue are discussed. Relative and absolute contraindications as well as artifacts and benign conditions are emphasized. DATA SOURCES: Sources include a compilation of the authors' experiences in academic and community liver transplantation centers. In addition, relevant medical literature was reviewed, as well as Web sites specializing in organ transplantation, such as Transplant Pathology Internet Services and the Organ Procurement and Transplantation Network. CONCLUSIONS: Malignancy and extensive necrosis in the liver are absolute contraindications to transplantation. Evaluation of macrosteatosis, fibrosis, hepatitis, and necrosis depends on the severity of disease and correlation with the clinical situation. Donor age of greater than 60 years does not preclude transplantation. Artifacts and benign conditions need to be understood to prevent wastage of precious organs and to ensure that an appropriate organ is provided for the recipient.
Subject(s)
Liver Transplantation , Tissue Donors , Biopsy , Contraindications , Donor Selection , Fatty Liver/pathology , Focal Nodular Hyperplasia/pathology , Frozen Sections , Hepatitis C, Chronic/pathology , Humans , Intraoperative Period , Liver/pathology , Liver Cirrhosis/pathology , Liver Neoplasms/pathology , Liver Transplantation/adverse effects , Liver Transplantation/pathology , Living Donors , Necrosis , Pathology, Surgical , Referral and Consultation , Risk Factors , Siderosis/pathology , Tissue and Organ HarvestingABSTRACT
BACKGROUND: The size of the liver donor graft is a major concern in living donor liver transplantation. Rapid regeneration is essential for the survival of these grafts. The purpose of this study was to investigate the effect of remote ischemic preconditioning (RIPC) on liver regeneration in a rat small-for-size liver transplantation model. METHODS: We established rat models of small-for-size liver transplantation (30%) in the presence or absence (control) of remote ischemic preconditioning. We observed liver mass regeneration, serum alanine aminotransferase, hepatic pathologic alterations, flow cytometry, and Ki-67 antigen immunohistochemistry. In addition, using Western blotting and reverse-transcriptase-polymerase chain reaction, we assessed the activation of cell cycle progression as well as tumor necrosis factor-α and interleukin-6 expression. RESULTS: Compared with the control group, serum alanine aminotransferase activity was significantly lower and histopathology changes were significantly attenuated in the RIPC group. Remote ischemic preconditioning induced a high level of interleukin-6 mRNA in small grafts, but suppressed the expression of tumor necrosis factor-α. The proliferation index, indicated by the S-phase and G2/M-phase ratio [(S+G2/M)/(G0/G1+S+G2/M)], was signiï¬cantly increased in the RIPC group at 24 h (58.25% ± 0.506% versus 53.405% ± 1.25%; P = .007). Meanwhile, cell cycle progression and regeneration (Ki-67) were initiated early in liver grafts treated with RIPC. CONCLUSIONS: These results suggest that RIPC can protect liver cells against ischemia reperfusion injury in the small grafts and enhance liver regeneration. Interleukin-6 may be a critical mediator in the stimulatory effect on liver cell regeneration, which may make RIPC valuable as a hepatoprotective modality.
Subject(s)
Cell Proliferation , Hepatocytes/pathology , Ischemic Preconditioning/methods , Liver Transplantation/pathology , Liver/pathology , Models, Animal , Alanine Transaminase/blood , Animals , Cell Cycle/physiology , Graft Survival/physiology , Interleukin-6/blood , Liver/physiology , Liver/surgery , Liver Regeneration/physiology , Liver Transplantation/physiology , Male , Rats , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/bloodABSTRACT
BACKGROUND: γ-Aminobutyric acid exists throughout the body, and the brain γ-aminobutyric acid receptor (GABAR) regulation reduces oxidative stress (OS). Effects of GABAR regulation in the liver are unknown. Ischemia or reperfusion injury after orthotopic liver transplantation (OLT) or shear stress after split OLT (SOLT) with a small-for-size graft causes OS-induced graft damage. Here, the strategic potential of graft pretreatment in vivo and ex vivo by GABAR regulation was investigated. MATERIALS AND METHODS: Recipient rats were divided into seven groups according to the graft pretreatments and graft types: (1) laparotomy, (2) OLT, (3) GABAR regulation in vivo and OLT, (4) GABAR regulation ex vivo and OLT, (5) SOLT, (6) GABAR regulation in vivo and SOLT, and (7) GABAR regulation ex vivo and SOLT. Survival study, biochemical assays, histopathologic or immunohistologic assessments, and Western blotting were performed at 6 h after OLT or SOLT. RESULTS: Graft pretreatment in vivo prolonged survival after SOLT. Histopathologic and biochemical profiles verified that graft pretreatment in vivo reduced graft damage after OLT or SOLT. Immunohistologically, graft pretreatment in vivo prevented apoptotic inductions after OLT or SOLT. The 4-hydroxynonenal confirmed the OS after OLT or SOLT, and graft pretreatment in vivo improved the OS. Graft pretreatment in vivo decreased ataxia-telangiectasia-mutated kinase and H2AX after OLT or SOLT. Graft pretreatment in vivo increased phosphatidylinositol 3 kinase and Akt after SOLT. In contrast, GABAR regulation ex vivo did not work. CONCLUSIONS: Graft pretreatment in vivo, not ex vivo, prevented the ischemia or reperfusion injury-mediated OS after OLT or SOLT via the ataxia-telangiectasia-mutated kinase/H2AX pathway and the shear stress-mediated OS after SOLT with small-for-size graft via the phosphatidylinositol 3 kinase/Akt pathway.
Subject(s)
GABA Agonists/pharmacology , Liver Transplantation/pathology , Liver/drug effects , Muscimol/pharmacology , Receptors, GABA/metabolism , Reperfusion Injury/prevention & control , Animals , Apoptosis/drug effects , Apoptosis/physiology , Graft Survival/drug effects , Graft Survival/physiology , Lipid Peroxidation/drug effects , Lipid Peroxidation/physiology , Liver/metabolism , Liver/surgery , Liver Transplantation/physiology , Models, Animal , Rats , Rats, Inbred Lew , Receptors, GABA/drug effects , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Stress, Mechanical , Superoxide Dismutase/metabolism , Superoxide Dismutase-1ABSTRACT
In western countries, hepatocellular carcinoma (HCC) is a major reason for orthotopic liver transplantation (OLT) with estimated recurrence rates between 15% and 20%. This selective literature review addresses follow-up care after OLT in HCC and current treatment options. Recurrence prediction is based on pathological tumor stage, vascular invasion, serum alfafetoprotein levels, and histological differentiation, but further advances are expected by molecular profiling techniques. Lower levels of immunosuppressive agents are associated with a lower risk for HCC recurrence. Retrospective studies indicate that mammalian target of rapamycin (mTOR) inhibitors as immunosuppression reduce the risk of HCC recurrence. However, prospective studies supporting this potential advantage of mTOR inhibitors are still lacking, and higher rejection rates were reported for sirolimus after OLT in HCC. Prognosis is poor in recurrent HCC, a longer interval between OLT and recurrence and feasibility of surgical resection are associated with improved survival. Systemic treatment with sorafenib is the current standard of care in patients with advanced-stage HCC not suitable for locoregional therapy. After OLT, combination of an mTOR inhibitor with sorafenib is feasible and frequently used in clinical practice. As safety and efficacy data are still limited, close clinical monitoring is mandatory.
Subject(s)
Carcinoma, Hepatocellular/diagnosis , Liver Neoplasms/diagnosis , Liver Neoplasms/therapy , Liver Transplantation/pathology , Neoplasm Recurrence, Local , Animals , Humans , Immunosuppressive Agents/therapeutic use , Niacinamide/analogs & derivatives , Niacinamide/therapeutic use , Phenylurea Compounds/therapeutic use , Risk Factors , Sorafenib , TOR Serine-Threonine Kinases/metabolism , Time Factors , Treatment OutcomeABSTRACT
UNLABELLED: Ischemia-reperfusion injury (IRI) is a major limiting event for successful liver transplantation, and CD4+ T cells and invariant natural killer T (iNKT) cells have been implicated in promoting IRI. We hypothesized that hepatic overexpression of CD39, an ectonucleotidase with antiinflammatory functions, will protect liver grafts after prolonged cold ischemia. CD39-transgenic (CD39tg) and wildtype (WT) mouse livers were transplanted into WT recipients after 18 hours cold storage and pathological analysis was performed 6 hours after transplantation. Serum levels of alanine aminotransferase and interleukin (IL)-6 were significantly reduced in recipients of CD39tg livers compared to recipients of WT livers. Furthermore, less severe histopathological injury was demonstrated in the CD39tg grafts. Immune analysis revealed that CD4+ T cells and iNKT cells were significantly decreased in number in the livers of untreated CD39tg mice. This was associated with a peripheral CD4+ T cell lymphopenia due to defective thymocyte maturation. To assess the relative importance of liver-resident CD4+ T cells and iNKT cells in mediating liver injury following extended cold preservation and transplantation, WT mice depleted of CD4+ T cells or mice genetically deficient in iNKT cells were used as donors. The absence of CD4+ T cells, but not iNKT cells, protected liver grafts from early IRI. CONCLUSION: Hepatic CD4+ T cells, but not iNKT cells, play a critical role in early IRI following extended cold preservation in a liver transplant model.
Subject(s)
Antigens, CD/metabolism , Apyrase/metabolism , CD4-Positive T-Lymphocytes/pathology , Liver Transplantation/pathology , Lymphopenia/pathology , Reperfusion Injury/prevention & control , Up-Regulation , Alanine Transaminase/blood , Animals , Antigens, CD/genetics , Apyrase/genetics , CD4-Positive T-Lymphocytes/immunology , Disease Models, Animal , Interleukin-6/blood , Killer Cells, Natural/pathology , Liver Transplantation/immunology , Lymphopenia/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , T-Lymphocytes, Regulatory/pathologyABSTRACT
PURPOSE: To evaluate the relative enhancement of liver, pancreas, focal nodular hyperplasia (FNH), pancreas-to-liver index, and FNH-to-liver index in the hepatic arterial dominant phase (HADP) after injection of hepatocyte-specific MRI contrast agents, gadoxetic acid and gadobenate dimeglumine, on 3 and 1.5 Tesla (T) MRI in the same patient. MATERIALS AND METHODS: The MRI database was retrospectively searched to identify consecutive patients who underwent abdominal MRI at 3T and 1.5T systems, using both 0.025 mmol/kg gadoxetic acid-enhanced and 0.05 mmol/kg gadobenate dimeglumine-enhanced MRI at the same magnetic strength field system. 22 patients were identified, 10 were scanned at 3T system and 12 at 1.5T system. The enhancement of liver, pancreas, and FNH was evaluated quantitatively on MR images. RESULTS: The relative enhancement of liver in HADP in the gadobenate dimeglumine-enhanced group in all subjects was significantly higher than that in gadoxetic acid-enhanced group (P = 0.023). The gadobenate dimeglumine-enhanced group in HADP had better relative enhancement of pancreas and FNH, pancreas-to-liver index, and FNH-to-liver index than gadoxetic acid-enhanced group, but the difference was not statistically significant. CONCLUSION: The 0.05 mmol/kg gadobenate dimeglumine-enhanced abdominal MRI studies at 3T and 1.5T MR systems are superior in relative enhancement of the liver in HADP to 0.025 mmol/kg gadoxetic acid-enhanced MRI. This type of assessment may provide comparative effectiveness data.
Subject(s)
Contrast Media/administration & dosage , Focal Nodular Hyperplasia/diagnosis , Focal Nodular Hyperplasia/pathology , Gadolinium DTPA , Hepatocytes/pathology , Image Enhancement/methods , Image Interpretation, Computer-Assisted/methods , Liver/blood supply , Liver/pathology , Magnetic Resonance Imaging/methods , Meglumine/analogs & derivatives , Organometallic Compounds , Pancreas/blood supply , Pancreas/pathology , Adenoma, Liver Cell/diagnosis , Adenoma, Liver Cell/pathology , Adult , Carcinoma, Hepatocellular/diagnosis , Carcinoma, Hepatocellular/pathology , Female , Hemangioma/diagnosis , Hemangioma/pathology , Hepatic Artery/pathology , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/pathology , Liver Neoplasms/diagnosis , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Liver Transplantation/pathology , Male , Mass Screening , Middle Aged , Retrospective Studies , Sensitivity and SpecificityABSTRACT
BACKGROUND: Transplant recipients are at risk of posttransplant lymphoproliferative disease (PTLD). METHODS: Thirty-six pediatric transplant recipients were evaluated (18 hematopoietic stem cell and 18 liver recipients; 12 had PTLD). We studied 207 longitudinal plasma samples from these recipients for three markers of B-cell activation or clonality: immunoglobulin free light chains (FLCs), soluble CD30 (sCD30), and monoclonal immunoglobulins (M-proteins). RESULTS: Kappa FLCs, lambda FLCs, and sCD30 were elevated in 20.8%, 28.0%, and 94.2% of plasma specimens, respectively. Free light chain and sCD30 levels increased significantly 1.18 to 1.82 fold per log10 Epstein-Barr virus (EBV) load in peripheral blood. Five PTLD cases manifested elevated FLCs with an abnormal kappa/lambda ratio, suggesting monoclonal FLC production. M-proteins were present in 91% of PTLD cases versus 50% to 67% of other recipients with high or low EBV loads (P=0.13). Concordance of FLCs, M-proteins, and PTLD tumor light chain restriction was imperfect. For example, one PTLD case with an IgG lambda M-protein had a tumor that was kappa restricted, and another case with an M-protein had a T-cell PTLD. In an additional case, an IgM kappa M-protein and excess kappa FLCs were both detected in plasma at PTLD diagnosis; although the tumor was not restricted at diagnosis, kappa restriction was present 5 years later when the PTLD relapsed. CONCLUSIONS: Plasma markers of B-cell dysfunction are frequent after transplantation and associated with poor EBV control. These abnormal markers may be produced by oligoclonal B-cell populations or PTLD tumor cells and could potentially help identify recipients at high risk of PTLD.
Subject(s)
B-Lymphocytes/pathology , Hematopoietic Stem Cell Transplantation , Herpesvirus 4, Human , Immunoglobulin Light Chains/blood , Ki-1 Antigen/blood , Liver Transplantation , Lymphocyte Activation/physiology , Viral Matrix Proteins/blood , Adolescent , Biomarkers/blood , Child , Child, Preschool , Female , Humans , Immunoglobulin kappa-Chains/blood , Immunoglobulin lambda-Chains/blood , Infant , Liver Transplantation/pathology , Lymphoproliferative Disorders/epidemiology , Male , Retrospective Studies , Risk Factors , Transplantation , Viral Load , Virus Replication/physiology , Young AdultABSTRACT
Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.
Subject(s)
Carcinoma, Hepatocellular/ultrastructure , Contrast Media/administration & dosage , Image Enhancement/methods , Image Interpretation, Computer-Assisted/methods , Liver Diseases/diagnostic imaging , Liver Neoplasms/diagnostic imaging , Liver/diagnostic imaging , Anaphylaxis/chemically induced , Anaphylaxis/mortality , Biopsy, Needle/methods , Carcinoma, Hepatocellular/pathology , Carcinoma, Hepatocellular/surgery , Cell Transformation, Neoplastic/pathology , Contraindications , Contrast Media/adverse effects , Diagnosis, Differential , Drug Hypersensitivity/etiology , Drug Hypersensitivity/mortality , Drug Interactions , Ferric Compounds/adverse effects , Fluorocarbons/adverse effects , Humans , Iron/adverse effects , Liver/pathology , Liver/surgery , Liver Cirrhosis/diagnostic imaging , Liver Cirrhosis/pathology , Liver Diseases/pathology , Liver Diseases/surgery , Liver Neoplasms/pathology , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Liver Transplantation/pathology , Oxides/adverse effects , Phospholipids/adverse effects , Risk Factors , Sulfur Hexafluoride/adverse effects , Ultrasonography, Doppler/methods , Ultrasonography, Interventional/methodsABSTRACT
Hepatitis C virus (HCV) infection is a major cause of chronic liver disease worldwide. The interplay between the virus and host innate and adaptive immune responses determines the outcome of infection. There is increasing evidence that host neutralizing responses play a relevant role in the resulting pathogenesis. Furthermore, viral evasion from host neutralizing antibodies has been revealed to be an important contributor in leading both to viral persistence in acute liver graft infection following liver transplantation, and to chronic viral infection. The development of novel model systems to study HCV entry and neutralization has allowed a detailed understanding of the molecular mechanisms of virus-host interactions during antibody-mediated neutralization. The understanding of these mechanisms will ultimately contribute to the development of novel antiviral preventive strategies for liver graft infection and an urgently needed vaccine. This review summarizes recent concepts of the role of neutralizing antibodies in viral clearance and protection, and highlights consequences of viral escape from neutralizing antibodies in the pathogenesis of HCV infection.
Subject(s)
Antibodies, Neutralizing/immunology , Hepacivirus/immunology , Hepacivirus/pathogenicity , Hepatitis C, Chronic/pathology , Animals , B-Lymphocytes/immunology , B-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Hepatitis C Antibodies/immunology , Hepatitis C, Chronic/immunology , Hepatitis C, Chronic/virology , Humans , Immune Evasion , Immunity, Humoral , Liver/immunology , Liver/virology , Liver Transplantation/immunology , Liver Transplantation/pathology , Viral Envelope Proteins/immunology , Virus InternalizationABSTRACT
BACKGROUND: Ischemia/reperfusion injury is an obstacle especially in steatotic livers, including those with steatosis induced by acute toxic stress. Recently, a modified histidine-tryptophan-ketoglutarate (HTK) solution, HTK-N, has been developed. This solution contains N-acetylhistidine, amino acids, and iron chelators. This study was designed to test the effects of HTK-N on preservation injury to rat livers after acute toxic injury. METHODS: Microvesicular steatosis was induced by a single dose of ethanol (8 g/kg BW). Livers were harvested and stored at 4 °C for 8 h with HTK or HTK-N before transplantation. Tissue and blood samples were taken at 1, 8, and 24 h after reperfusion to compare serum liver enzymes (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase), standard histology, and immunohistochemistry for myeloperoxidase (MPO), caspase-3, and inducible nitric oxide synthase. Survival was compared after 1 week. For statistics, Analysis of Variance and t test were used. RESULTS: HTK-N improved survival from 12.5% in HTK to 87.5% (p < 0.05). Furthermore, liver enzymes were decreased to 2-75% of HTK values (p < 0.05). Necrosis and leukocyte infiltration and MPO, caspase-3, and iNOS expression after transplantation were decreased (p < 0.05). CONCLUSIONS: This study demonstrates that HTK-N protects liver grafts with microvesicular steatosis caused by acute toxic injury from cold ischemic injury better than standard HTK most likely via inhibition of hypoxic injury and oxidative stress and amelioration of the inflammatory reaction occurring upon reperfusion.
Subject(s)
Fatty Liver/pathology , Histidine/analogs & derivatives , Liver Transplantation , Organ Preservation Solutions , Alanine Transaminase/blood , Animals , Aspartate Aminotransferases/blood , Cold Temperature , Ethanol/toxicity , Fatty Liver/surgery , Female , Glucose/chemistry , Histidine/analysis , Iron Chelating Agents , L-Lactate Dehydrogenase/blood , Liver/blood supply , Liver/pathology , Liver Transplantation/mortality , Liver Transplantation/pathology , Mannitol/chemistry , Microvessels/drug effects , Microvessels/pathology , Potassium Chloride/chemistry , Procaine/chemistry , Rats , Rats, Sprague-Dawley , Survival RateSubject(s)
Acute Kidney Injury/diagnosis , Kidney Failure, Chronic/diagnosis , Organ Transplantation , Postoperative Complications/diagnosis , Acute Kidney Injury/pathology , Age Factors , Calcineurin Inhibitors , Comorbidity , Heart Transplantation/pathology , Humans , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Kidney/pathology , Kidney Failure, Chronic/pathology , Kidney Function Tests , Liver Transplantation/pathology , Lung Transplantation/pathology , Organ Transplantation/pathology , Pancreas Transplantation/pathology , Postoperative Complications/pathology , Risk FactorsABSTRACT
A female patient with primary sclerosing cholangitis developed a cholangiocarcinoma (Klatskin tumor) at the age of 42 years. It was successfully resected by hemihepatectomy and hepaticojejunostomy. In the next 15 years she had recurrent episodes of bacterial cholangitis and had to be hospitalized several times a year for intravenous antibiotics. At the same time the sclerosing cholangitis progressed and she developed liver cirrhosis. The patient, who was never willing to give up, underwent liver transplantation by receiving the left liver lobe of her daughter (living donor). Postoperatively she suffered from severe complications including a biliary leak, sepsis, intraabdominal abscesses and cachexia. Soon after she was dismissed by the transplantation center, she was admitted to our hospital in a very poor condition. She refused any further intensive care and died, with the well functioning donated left liver lobe of the daughter dying with her.
Subject(s)
Cholangitis, Sclerosing/surgery , Cholangitis/pathology , Klatskin Tumor/surgery , Liver Cirrhosis/surgery , Liver Neoplasms/surgery , Liver Transplantation/pathology , Living Donors , Postoperative Complications/pathology , Abscess/pathology , Abscess/surgery , Adult , Cholangitis/surgery , Cholangitis, Sclerosing/pathology , Ethics, Medical , Fatal Outcome , Female , Follow-Up Studies , Hepatectomy/ethics , Humans , Jejunostomy/ethics , Klatskin Tumor/pathology , Liver Cirrhosis/pathology , Liver Function Tests/ethics , Liver Neoplasms/pathology , Liver Transplantation/ethics , Living Donors/ethics , Middle Aged , Postoperative Complications/surgery , Recurrence , Reoperation/ethics , Surgical Wound Infection/pathology , Surgical Wound Infection/surgery , Tissue Adhesions/pathology , Tissue Adhesions/surgeryABSTRACT
BACKGROUND: Bone marrow-derived hematopoietic stem cells (BM-HSCs) have been shown to act as source for hepatic regeneration in rodent models; however, their ability to participate in human liver regeneration remains controversial. The aim of this study was to investigate the origin of hepatocytes in sex-mismatched cases of orthotopic liver transplantation in longitudinally performed liver biopsies. METHODS: Paraffin-embedded liver biopsy samples of 14 patients after sex-mismatched (female-to-male) liver transplantation were investigated. Biopsies were taken at multiple time points and subjected to histologic examination. Immunohistochemical staining with a hepatocyte-specific antibody and fluorescent in situ hybridization for visualization of Y chromosomes were performed to analyze the presence of recipient-derived hepatocytes. RESULTS: We analyzed 30 liver biopsy samples ranging from 1 week to more than 3 years after transplantation. There was no evidence for recipient-derived hepatocytes in liver transplants at any time point. We were able to detect recipient-specific chromosomal status in inflammatory cells within the liver but not within hepatocytes. Results were independent of liver injury at the time of biopsy, caused by hepatitis C recurrence or rejection episodes. CONCLUSIONS: Our results show no evidence for involvement of BM-HSCs in liver regeneration after orthotopic liver transplantation. We think that recipient BM-HSC-derived hepatocyte repopulation is a very rare event at best and is not of clinical relevance.
Subject(s)
Hepatocytes/pathology , Liver Transplantation/pathology , Liver/pathology , Sex Characteristics , Transplantation/pathology , Adult , Aged , Biopsy , Bone Marrow Cells/pathology , Chromosomes, Human, Y , Female , Hematopoietic Stem Cells/pathology , Humans , In Situ Hybridization, Fluorescence , Liver Regeneration , Male , Middle Aged , Retrospective Studies , Time FactorsABSTRACT
BACKGROUND: Liver ischemia-reperfusion injury (IRI) is a known risk factor for the postoperative outcome of patients undergoing liver surgery/transplantation. Attempts to protect from organ damage require multidisciplinary strategies and are of emerging interest in view of patients with higher age and American Society of Anesthesiology status. Ischemic preconditioning has been successfully applied to prevent from IRI during liver resection/transplantation. Because even short periods of ischemia during preconditioning inevitably lead to hypoxia and formation of anti-inflammatory/cytoprotective acting adenosine, we reasoned that short nonischemic hypoxia also protects against hepatic IRI. METHODS: Mice underwent hypoxic preconditioning (HPC) by breathing 10% oxygen for 10 min followed by 10 min of 21% oxygen before left liver lobe ischemia (45 min) and reperfusion (4 hr). The interactions of hypoxiaâadenosineâadenosine receptors were tested by pharmacologic antagonism at adenosine receptor (AR) sites in wild-type mice and in mice with genetic deletions at the A1, A2A, A2B, and A3 ARs. Hepatocellular damage, inflammation, and metabolic effects were quantified by enzyme activities, cytokines, liver myeloperoxidase, blood adenosine, and tissue AMP, respectively. RESULTS: Hepatoprotection by HPC was significant in wild-type and A1, A2A, and A3 AR knockout mice as quantified by lower alanine aminotransferase serum activities, cytokine levels, histologic damage scores, tissue myeloperoxidase concentrations, and preserved AMP concentrations. Protection by HPC was blunted in mice pretreated with the A2B AR antagonist MRS1754 or in A2B AR knockout mice. CONCLUSIONS: Because liver protective effects of HPC are negated when the A2B receptor is nonfunctional, the hypoxiaâadenosineâA2B receptor pathway plays a critical role in the prevention of warm IRI in vivo. Hypoxic activation of this pathway warrants use of selective A2B AR agonists or even intermittent hypoxia (e.g., in deceased organ donors) to protect from liver IRI.