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1.
Aliment Pharmacol Ther ; 47(5): 631-644, 2018 03.
Article in English | MEDLINE | ID: mdl-29271504

ABSTRACT

BACKGROUND: Validated diagnostic tools that are accurate, cost effective and acceptable to patients are required for disease stratification and monitoring in NAFLD. AIMS: To investigate the performance and cost of multiparametric MRI alongside existing biomarkers in the assessment of NAFLD. METHODS: Adult patients undergoing standard of care liver biopsy for NAFLD were prospectively recruited at two UK liver centres and underwent multiparametric MRI, blood sampling and transient elastography withing 2 weeks of liver biopsy. Non-invasive markers were compared to histology as the gold standard. RESULTS: Data were obtained in 50 patients and 6 healthy volunteers. Corrected T1 (cT1) correlated with NAFLD activity score (ρ = 0.514, P < .001). cT1, enhanced liver fibrosis (ELF) test and liver stiffness differentiated patients with simple steatosis and NASH with AUROC (95% CI) of 0.69 (0.50-0.88), 0.87 (0.77-0.79) and 0.82 (0.70-0.94) respectively and healthy volunteers from patients with AUROC (95% CI) of 0.93 (0.86-1.00), 0.81 (0.69-0.92) and 0.89 (0.77-1.00) respectively. For the risk stratification of NAFLD, multiparametric MRI could save £150,218 per 1000 patients compared to biopsy. Multiparametric MRI did not discriminate between individual histological fibrosis stages in this population (P = .068). CONCLUSIONS: Multiparametric MRI accurately identified patients with steatosis, stratifies those with NASH or simple steatosis and reliably excludes clinically significant liver disease with superior negative predictive value (83.3%) to liver stiffness (42.9%) and ELF (57.1%). For the risk stratification of NAFLD, multiparametric MRI was cost effective and, combined with transient elastography, had the lowest cost per correct diagnosis.


Subject(s)
Liver/diagnostic imaging , Magnetic Resonance Imaging , Non-alcoholic Fatty Liver Disease/diagnosis , Adolescent , Adult , Aged , Biopsy , Cost-Benefit Analysis , Elasticity Imaging Techniques/economics , Elasticity Imaging Techniques/methods , Female , Healthy Volunteers , Humans , Liver/pathology , Liver Cirrhosis/diagnosis , Liver Cirrhosis/economics , Magnetic Resonance Imaging/economics , Magnetic Resonance Imaging/methods , Male , Middle Aged , Non-alcoholic Fatty Liver Disease/economics , Non-alcoholic Fatty Liver Disease/pathology , Predictive Value of Tests , Young Adult
2.
Am J Transplant ; 16(10): 2816-2835, 2016 10.
Article in English | MEDLINE | ID: mdl-27273869

ABSTRACT

The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.


Subject(s)
Graft Rejection/etiology , Graft Rejection/pathology , Isoantibodies/immunology , Liver Transplantation/adverse effects , Allografts , Humans , Research Report
3.
Am J Transplant ; 16(11): 3235-3245, 2016 11.
Article in English | MEDLINE | ID: mdl-27192971

ABSTRACT

The demand for liver transplantation (LT) exceeds supply, with rising waiting list mortality. Utilization of high-risk organs is low and a substantial number of procured livers are discarded. We report the first series of five transplants with rejected livers following viability assessment by normothermic machine perfusion of the liver (NMP-L). The evaluation protocol consisted of perfusate lactate, bile production, vascular flows, and liver appearance. All livers were exposed to a variable period of static cold storage prior to commencing NMP-L. Four organs were recovered from donors after circulatory death and rejected due to prolonged donor warm ischemic times; one liver from a brain-death donor was declined for high liver function tests (LFTs). The median (range) total graft preservation time was 798 (range 724-951) min. The transplant procedure was uneventful in every recipient, with immediate function in all grafts. The median in-hospital stay was 10 (range 6-14) days. At present, all recipients are well, with normalized LFTs at median follow-up of 7 (range 6-19) months. Viability assessment of high-risk grafts using NMP-L provides specific information on liver function and can permit their transplantation while minimizing the recipient risk of primary graft nonfunction. This novel approach may increase organ availability for LT.


Subject(s)
Liver Transplantation , Liver/metabolism , Organ Preservation , Perfusion/methods , Tissue Donors/supply & distribution , Tissue Survival , Tissue and Organ Procurement/methods , Adult , Aged , Allografts , Female , Follow-Up Studies , Graft Rejection/prevention & control , Humans , Liver/blood supply , Liver Function Tests , Male , Middle Aged , Outcome Assessment, Health Care , Pilot Projects , Primary Graft Dysfunction/prevention & control , Warm Ischemia
4.
Postgrad Med J ; 89(1058): 685-92, 2013 Dec.
Article in English | MEDLINE | ID: mdl-23924687

ABSTRACT

BACKGROUND: Fibroscan is a quick, non-invasive technique used to measure liver stiffness (kPa), which correlates with fibrosis. To achieve a valid liver stiffness evaluation (LSE) the operator must obtain all the following three criteria: (1) ≥10 successful liver stiffness measurements; (2) IQR/median ratio <0.30 and (3) ≥60% measurement success rate. OBJECTIVES: To assess the operator training requirements and the importance of adhering to the LSE validity criteria in routine clinical practice. METHODS: We retrospectively analysed the LSE validity rates of 2311 Fibroscans performed (1 August 2008 to 31 July 2011) in our tertiary liver outpatients department at the University Hospital Birmingham, UK. The diagnostic accuracy of Fibroscan was assessed in 153 patients, by comparing LSE (valid and invalid) with the modified Ishak fibrosis stage on liver biopsy. RESULTS: Learning curve analysis highlighted that the greatest improvement in validity of LSE rates occurs in the operator's first 10 Fibroscans, reaching 64.7% validity by the 50th Fibroscan. The correlation between LSE and the fibrosis stage on liver biopsy was superior in patients with a valid LSE (n=97) compared with those with an invalid LSE (n=56) (rs 0.577 vs 0.259; p=0.022). Area under receiving operating characteristics for significant fibrosis was greater when LSE was valid (0.83 vs 0.66; p=0.048). Using an LSE cut-off of 8 kPa, the negative predictive value of valid LSE was superior to invalid LSE for the detection of significant (84% vs 71%) and advanced fibrosis (100% vs 93%). CONCLUSIONS: Fibroscan requires minimal operator training (≥10 observed on patients), and when a valid LSE is obtained, it is an accurate tool for excluding advanced liver fibrosis. To ensure the diagnostic accuracy of Fibroscan it is essential that the recommended LSE validity criteria are adhered to in routine clinical practice.


Subject(s)
Clinical Competence , Elasticity Imaging Techniques , Guideline Adherence , Health Personnel/education , Liver Cirrhosis/diagnosis , Liver/pathology , Area Under Curve , Biopsy , Clinical Competence/standards , Elasticity Imaging Techniques/methods , Elasticity Imaging Techniques/standards , England , Female , Humans , Liver Cirrhosis/pathology , Male , Middle Aged , Practice Guidelines as Topic , Predictive Value of Tests , ROC Curve , Reproducibility of Results , Retrospective Studies , Sensitivity and Specificity , Severity of Illness Index , State Medicine
6.
J Clin Pathol ; 62(6): 519-24, 2009 Jun.
Article in English | MEDLINE | ID: mdl-19155239

ABSTRACT

AIMS: In the era of targeted therapeutics, histological typing of hepatobiliary carcinomas has major clinical implications. Little is known about the reproducibility of the pathological diagnosis of primary liver carcinomas. Therefore, this study aimed to evaluate the worldwide variation in the pathological expert diagnoses of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis. METHODS: A single set of slides was selected from 25 tumours, and this set was reviewed independently by 12 pathologists who have worldwide expertise in liver tumours. Reproducibility of the diagnoses was evaluated by Light's kappa, and diagnoses were clustered by multidimensional scaling. Immunohistochemistry was performed after histological review. RESULTS: The interobserver reproducibility for diagnosis of hepatocellular carcinoma subtypes and cholangiocarcinomas was poor (kappa 0.23-0.52), even when the experts considered that the diagnosis required no additional stains or clinical information. Interestingly, multidimensional scaling revealed three main clusters of tumours: hepatocellular carcinoma with no other specifications (n = 13), fibrolamellar hepatocellular carcinoma (n = 3) and cholangiocarcinoma (n = 9). Using immunohistochemistry, these histological clusters correlated with expression of anti-hepatocyte and anti-cytokeratin 19 (p<0.001). CONCLUSIONS: The results demonstrate the poor reproducibility among experts of the pathological diagnosis of primary liver carcinomas with fibrous stroma in patients who did not have cirrhosis, and highlight that the systematic use of immunohistochemistry may improve the diagnostic accuracy.


Subject(s)
Carcinoma, Hepatocellular/pathology , Cholangiocarcinoma/pathology , Liver Neoplasms/pathology , Medical Oncology/standards , Adolescent , Adult , Aged , Antibodies/analysis , Biomarkers, Tumor/analysis , Carcinoembryonic Antigen/immunology , Carcinoma, Hepatocellular/chemistry , Child , Cholangiocarcinoma/chemistry , Cluster Analysis , Diagnosis, Differential , Female , Hepatocytes/pathology , Humans , Immunohistochemistry , Keratin-19/immunology , Keratin-7/immunology , Keratins/analysis , Liver Neoplasms/chemistry , Male , Middle Aged , Reproducibility of Results , Young Adult
7.
Am J Transplant ; 8(9): 1931-41, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18671674

ABSTRACT

Late allograft dysfunction is a significant problem following liver transplantation and its pathogenesis is uncertain. HLA-C is the major inhibitory ligand for killer immunoglobulin-like receptors (KIRs) that regulate the cytotoxic activity of natural killer (NK) cells. HLA-C alleles can be allocated into two groups, termed HLA-C1 and HLA-C2, based on their KIR specificity. HLA-C2 interactions are more inhibiting to NK cell activation. We studied the clinical importance of HLA-C genotype in a large liver transplant cohort and found that possession of at least one HLA-C2 allele by the donor allograft was associated with less histological evidence of chronic rejection and graft cirrhosis, a 16.2% reduction in graft loss (p = 0.003) (hazard ratio: 2.7, 95% CI 1.4-5.3) and a 13.6% improvement in patient survival (p = 0.01) (hazard ratio: 1.9, 95% CI 1.1-3.3) at 10 years. Transplantation of an HLA-C2 homozygous allograft led to a particularly striking 26.5% reduction in graft loss (p < 0.001) (hazard ratio: 7.2, 95% CI 2.2-23.0) at 10 years when compared to HLA-C1 homozygous allografts. Donor HLA-C genotype is therefore a major determinant of clinical outcome after liver transplantation and reveals the importance of NK cells in chronic rejection and graft cirrhosis. Modulation of HLA-C and KIR interactions represents an important novel approach to promote long-term graft and patient survival.


Subject(s)
Graft Rejection/epidemiology , HLA-C Antigens/genetics , Liver Transplantation/immunology , Tissue Donors , Adult , Alleles , Cohort Studies , Female , Fibrosis/epidemiology , Fibrosis/pathology , Follow-Up Studies , Genotype , Graft Rejection/pathology , Graft Survival/genetics , Heterozygote , Histocompatibility Testing , Homozygote , Humans , Incidence , Kaplan-Meier Estimate , Killer Cells, Natural/immunology , Killer Cells, Natural/transplantation , Male , Multivariate Analysis , Receptors, KIR/immunology , Survival Analysis , Time Factors , Treatment Outcome , United Kingdom/epidemiology
8.
Eur J Surg Oncol ; 34(7): 782-6, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18160247

ABSTRACT

AIM: To compare the effects of preoperative chemotherapy on liver parenchyma morphology, as well as morbidity and mortality after liver resection for colorectal liver metastases. METHODS: Prospectively collected data on 173 patients undergoing liver resection for CLM between 1/2003 and 9/2005 was analysed in three groups: A: preoperative oxaliplatin (Ox, n=70); B: other chemotherapeutic agents (OC, n=60); and C: surgery alone without chemotherapy (SA, n=43). Blood transfusion, hospital stay, operative procedure, peak postoperative bilirubin levels, complications and histopathology of the resected liver were compared. RESULTS: Intra-operative blood transfusion requirement (34%) and biliary complications (16%) was higher in patients receiving oxaliplatin-based chemotherapy (p=0.01 and p=0.06, respectively). Oxaliplatin-based chemotherapy was also associated with sinusoidal dilatation of mild grade in 52.8% vs. 26.6% and 23.3% patients (p=0.007 and p=0.004) in other groups, respectively. Steatosis was similarly distributed across the study group. Postoperative mortality was 2, 1 and 4 patients, respectively (p=ns). CONCLUSION: Oxaliplatin-based preoperative chemotherapy is associated with vascular alterations in the liver parenchyma without significantly increasing the risk of steatosis, or postoperative morbidity and mortality.


Subject(s)
Antineoplastic Agents/administration & dosage , Colorectal Neoplasms/pathology , Liver Neoplasms/drug therapy , Organoplatinum Compounds/administration & dosage , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Camptothecin/administration & dosage , Camptothecin/adverse effects , Camptothecin/analogs & derivatives , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Hepatectomy/adverse effects , Humans , Irinotecan , Leucovorin/administration & dosage , Leucovorin/adverse effects , Liver Neoplasms/secondary , Liver Neoplasms/surgery , Middle Aged , Neoadjuvant Therapy , Organoplatinum Compounds/adverse effects , Oxaliplatin , Prospective Studies , Survival Analysis
9.
Histopathology ; 49(5): 450-65, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17064291

ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is an important complication of the metabolic syndrome, which is becoming an increasingly common cause of chronic liver disease. Histological changes typically mainly affect perivenular regions of the liver parenchyma and include an overlapping spectrum of steatosis, steatohepatitis and persinusoidal or pericellular fibrosis, in some cases leading to cirrhosis. Once cirrhosis has developed, typical hepatocellular changes are often no longer conspicuous, leading to such cases being mistakenly diagnosed as 'cryptogenic'. Portal inflammation, ductular reaction and periportal fibrosis can also be seen as part of the morphological spectrum of NAFLD, particularly in the paediatric population. Hepatocellular carcinoma has also been described as a complication of NAFLD-associated cirrhosis. NAFLD is also an important cofactor in other chronic liver diseases, especially hepatitis C. Histological assessments have an important role to play in the diagnosis and management of NAFLD. These include making the potentially important distinction between simple steatosis and steatohepatitis and providing pointers to the aetiology, including cases where a dual pathology exists. A number of systems have been devised for grading and staging the severity of fatty liver disease. These require further evaluation, but have a potentially important role to play in determining prognosis and monitoring therapeutic responses.


Subject(s)
Fatty Liver/etiology , Fatty Liver/pathology , Biopsy , Chronic Disease , Humans , Liver Cirrhosis/etiology , Liver Cirrhosis/pathology , Liver Diseases, Alcoholic/pathology , Metabolic Syndrome/complications , Metabolic Syndrome/pathology
10.
Br J Cancer ; 95(9): 1202-11, 2006 Nov 06.
Article in English | MEDLINE | ID: mdl-17024127

ABSTRACT

We used SEREX technology to identify novel tumour-associated antigens in patients with primary hepatocellular carcinoma and found serological responses to the polycomb group (PcG) protein BMI-1, which is overexpressed in a range of different tumour types. Further studies identified T-cell responses to both BMI-1 and another PcG protein, EZH2, in cancer patients and at relatively lower levels in some normal donors. We next identified several CD8+ T-cell epitopes derived from BMI-1 and EZH2 and demonstrated that EZH2-derived peptides elicited more significant interferon-gamma (IFN-gamma) release than BMI-1-derived peptides. That CD8(+) T cells were responsible for the observed responses was confirmed for EZH2 by both IFN-gamma capture assays and tetramer staining using an HLA-A0201-restricted, EZH2-derived YMSCSFLFNL (aa 666-674) epitope. The ability of YMSCSFLFNL (aa 666-674) to stimulate the in vitro expansion of specific T cells from peripheral blood lymphocytes was greatly enhanced when the CD25(+) T-cell population was depleted. EZH2-specific cytotoxic T lymphocyte clones specific for two HLA-A0201 epitopes were generated and found to recognise endogenously processed EZH2 in both HLA-matched fibroblasts and tumour cell lines. Given the widespread overexpression of PcG proteins in cancer and their critical role in oncogenesis, these data suggest that they may be useful targets for cancer immunotherapy.


Subject(s)
DNA-Binding Proteins/genetics , Neoplasms/pathology , Nuclear Proteins/genetics , Proto-Oncogene Proteins/genetics , Repressor Proteins/genetics , Transcription Factors/genetics , Amino Acid Sequence , Antigens, Neoplasm/analysis , Antigens, Neoplasm/genetics , Cell Line, Tumor , Cells, Cultured , Cytotoxicity, Immunologic/immunology , DNA-Binding Proteins/analysis , Enhancer of Zeste Homolog 2 Protein , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Interferon-gamma/biosynthesis , Interleukin-2 Receptor alpha Subunit/analysis , Leukocytes, Mononuclear/metabolism , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Neoplasms/genetics , Neoplasms/metabolism , Nuclear Proteins/analysis , Polycomb Repressive Complex 1 , Polycomb Repressive Complex 2 , Proto-Oncogene Proteins/analysis , RNA, Messenger/genetics , RNA, Messenger/metabolism , Repressor Proteins/analysis , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/analysis
11.
Transplant Proc ; 36(8): 2334-7, 2004 Oct.
Article in English | MEDLINE | ID: mdl-15561241

ABSTRACT

INTRODUCTION: Because of the tendency for preexisting diseases to recur following liver transplantation, studying the course of patients who were transplanted for their cryptogenic cirrhosis may reveal features of the original cause. We examined the clinicopathological posttransplant progression of patients transplanted due to cryptogenic cirrhosis with emphasis on the detection of posttransplant steatosis and steatohepatitis. METHODS: The data on all patients transplanted for cryptogenic cirrhosis and their routine 1-year posttransplant liver biopsies were compared to a control group of a randomized sample of patients transplanted for other indications matched for length of follow-up. The posttransplant histological diagnosis was based on the latest available biopsy. RESULTS: Among 1710 patients, 39 present with cryptogenic etiology survived at least 1 year after transplantation. The control group consisted of 78 patients. The mean ages of the two groups were 50.7 and 49.3 years and the mean follow-up periods 6.2 and 5.7 years, both of which were similar. There was a significantly greater prevalence of posttransplant steatosis and steatohepatitis among the cryptogenic group (37.5 vs 16.7%, P = .048). The difference in patients with at least moderate steatosis was more pronounced (18.8 vs 3.3%, P = .035). Half of these cases progressed to fibrosis and cirrhosis after 48 months. CONCLUSIONS: This study found a greater incidence of allograft steatosis and steatohepatitis among patients transplanted for cryptogenic cirrhosis compared with a control group. A significant proportion of these patients developed a picture resembling nonalcoholic steatohepatitis, which progressed to fibrosis and cirrhosis.


Subject(s)
Hepatitis, Chronic/pathology , Liver Transplantation/pathology , Adult , Biopsy , Fatty Liver/epidemiology , Fatty Liver/pathology , Female , Follow-Up Studies , Hepatitis, Chronic/epidemiology , Humans , Male , Middle Aged , Retrospective Studies , Time Factors
12.
Gut ; 52(2): 300-3, 2003 Feb.
Article in English | MEDLINE | ID: mdl-12524417

ABSTRACT

BACKGROUND: We report two cases of antidepressant induced cholestasis. CASE REPORTS: We describe the first reported case of acute cholestasis due to citalopram (selective serotonin reuptake inhibitor) occurring in a patient who also experienced obstetric cholestasis in association with each of three pregnancies; in a second patient cholestasis developed due to dothiepin (tricyclic antidepressant), and six years later due to paroxetine. In both cases liver biopsies showed features of a "pure" cholestasis with total resolution within 1-6 months after withdrawal of the causative drug. Immunostaining for the canalicular transporter, multidrug resistant protein 2 (MRP2), responsible for biliary secretion of several organic anions including bilirubin glucuronides, showed sustained expression in both biopsies as well as relocalisation with appearance of strong staining of the basolateral membrane of the hepatocyte. This finding has also not been reported previously. CONCLUSIONS: We postulate that intracellular redistribution of MRP2 may reflect an adaptive compensatory mechanism which helps in the elimination of the drug or its cholestatic metabolites from the hepatocyte back to the sinusoidal space and subsequent excretion in urine. Changes seen in these two patients differ from findings previously reported in rats where downregulation of mrp2 occurs in response to experimentally induced cholestasis. We speculate that the rat is more advanced than humans in its ability to downregulate canalicular transporter expression as protection against progressive intrahepatic cholestasis.


Subject(s)
Antidepressive Agents/adverse effects , Cholestasis/chemically induced , Mitochondrial Proteins , Ribosomal Proteins/metabolism , Saccharomyces cerevisiae Proteins , Acute Disease , Adult , Antidepressive Agents, Second-Generation/adverse effects , Antidepressive Agents, Tricyclic/adverse effects , Biopsy , Cholestasis/metabolism , Cholestasis/pathology , Citalopram/adverse effects , Dothiepin/adverse effects , Female , Humans , Immunohistochemistry , Liver/pathology , Male , Middle Aged , Paroxetine/adverse effects , Pregnancy , Pregnancy Complications/chemically induced , Pregnancy Complications/metabolism , Pregnancy Complications/pathology
13.
Hepatology ; 34(6): 1184-92, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11732008

ABSTRACT

Notch signaling is an evolutionarily conserved mechanism, used to regulate cell fate decisions. Four Notch receptors have been identified in man (Notch-1 to -4). In this study, semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry were used to examine the expression pattern of Notch receptor genes in whole adult human liver and isolated liver cell preparations. All 4 receptors were expressed in the adult liver, with no significant differences in the levels of Notch-1, -2, and -4 messenger RNA (mRNA) between normal and diseased liver. However, Notch-3 expression appeared to be increased in diseased tissue. The distribution of Notch-1 and -4 in normal tissue was similar, with Notch-1 also detectable at low levels in the sinusoidal endothelium. Notch-2 expression was more widely distributed, and detectable in hepatocytes, medium-sized bile ducts, and the sinusoidal endothelium. Notch-3 expression was seen on hepatocytes, with weaker expression detectable in portal veins, hepatic arteries, and the sinusoids. In normal liver tissue Notch-1, -2, and -3 were found to be coexpressed on bile duct epithelium; however, with the exception of Notch-3 in primary sclerosing cholangitis (PSC) livers, expression was absent on proliferating ductules in all disease states examined. Interestingly, the expression of Notch-2 and -3 was associated with numerous small vessels within the portal tract septa of diseased tissue. The absence of Notch receptor expression on proliferating bile ductules and its presence on neovessels suggests that Notch signaling may be important for normal bile duct formation and the aberrant neovascularization seen in diseased liver tissue.


Subject(s)
Liver Circulation , Liver/metabolism , Membrane Proteins/metabolism , Adult , Bile Ducts/growth & development , Cells, Cultured , Hepatocytes/metabolism , Humans , Immunohistochemistry , Liver Diseases/metabolism , Membrane Proteins/genetics , Membrane Proteins/physiology , Middle Aged , Neovascularization, Physiologic/physiology , Protein Isoforms/genetics , Protein Isoforms/metabolism , Protein Isoforms/physiology , RNA, Messenger/metabolism , Receptors, Notch , Reference Values , Reverse Transcriptase Polymerase Chain Reaction
14.
FASEB J ; 15(13): 2345-54, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11689460

ABSTRACT

Fas-mediated mechanisms of apoptosis are thought to be involved in the bile duct loss that characterizes diseases such as primary biliary cirrhosis (PBC). We have previously shown that activation of CD40 on hepatocytes can amplify Fas-mediated apoptosis; in the present study, we investigated interactions between CD40 and Fas in biliary epithelial cells (BEC). We report that the bile ducts in PBC liver tissue frequently express increased levels of Fas, Fas ligand (FasL), and CD40 associated with apoptotic BEC. The portal mononuclear infiltrate contains CD40L+ve T cells and macrophages, thereby demonstrating a potential mechanism for CD40 engagement in vivo. Primary cultures of human BEC also expressed Fas, FasL, and CD40 but not CD40L protein or mRNA. Activation of CD40 on BEC using recombinant CD40L increased transcriptional expression of FasL and induced apoptosis, which was inhibited by neutralizing antibodies to either Fas or FasL. Thus, CD40-induced apoptosis of BEC is mediated through Fas/FasL. We then investigated the intracellular signals and transcription factors activated in BEC and found that NF-kappaB and AP-1 were both activated after CD40 ligation. Increased functional NF-kappaB was seen early after CD40 ligation, but returned to baseline levels after 4 h. In contrast, the rapid up-regulation of AP-1 was sustained over 24 h. This study provides further functional evidence of the ability of CD40 to induce Fas/FasL-dependent apoptosis of liver epithelial cells supporting the importance of cross-talk between tumor necrosis factor (TNF) receptor family members as an amplification step in apoptosis induction. Sustained activation of AP-1 in the absence of NF-kappaB signaling may be a critical factor in determining the outcome of CD40 engagement.


Subject(s)
Apoptosis/physiology , Bile Ducts, Intrahepatic/physiology , CD40 Antigens/metabolism , NF-kappa B/physiology , Transcription Factor AP-1/physiology , fas Receptor/physiology , Bile Ducts, Intrahepatic/chemistry , Bile Ducts, Intrahepatic/cytology , CD40 Antigens/genetics , CD40 Ligand/metabolism , CD40 Ligand/pharmacology , Cells, Cultured , Epithelial Cells/chemistry , Epithelial Cells/cytology , Epithelial Cells/physiology , Fas Ligand Protein , Fluorescent Antibody Technique , Gene Expression Regulation , Humans , Immunohistochemistry , In Situ Nick-End Labeling , Liver Cirrhosis, Biliary/metabolism , Liver Cirrhosis, Biliary/pathology , Liver Cirrhosis, Biliary/physiopathology , Macrophages/chemistry , Macrophages/pathology , Membrane Glycoproteins/analysis , Membrane Glycoproteins/genetics , NF-kappa B/drug effects , NF-kappa B/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Signal Transduction , T-Lymphocytes/chemistry , T-Lymphocytes/pathology , Time Factors , Transcription Factor AP-1/drug effects , Transcription Factor AP-1/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Up-Regulation , fas Receptor/analysis
15.
Transplantation ; 71(11): 1566-72, 2001 Jun 15.
Article in English | MEDLINE | ID: mdl-11435966

ABSTRACT

BACKGROUND: The progression of parenchymal changes in liver allograft biopsies due to preservation-reperfusion injury (PRI) and their differentiation from rejection related changes is poorly understood. The aim of this study was to determine which changes in a 1-week posttransplant biopsy could be attributed to PRI and which to acute rejection. METHODS: One week protocol liver transplant biopsies from patients with mild PRI (day 1 AST<400 IU/L) were compared with those from patients with severe PRI (day 1 AST>2000 IU/L). Parenchymal changes (cholestasis, ballooning, steatosis, necrosis) and rejection-related inflammatory features (portal tract inflammation, bile duct inflammation, portal vein endothelial inflammation, hepatic vein endothelial inflammation, and centrilobular inflammation) were blindly assessed semiquantitatively. RESULTS: Fat, cholestasis, and hepatocyte ballooning were significantly worse in the severe PRI group, and these features showed no correlation with histological features related to acute rejection. Centrilobular hepatocyte necrosis correlated with hepatic venular endothelial inflammation and centrilobular inflammation but not with rejection related features in portal tracts or with PRI. These findings suggest that centrilobular necrosis is a manifestation of a rejection-related parenchymal injury and may involve different pathogenetic mechanisms to rejection-related features in portal tracts. CONCLUSIONS: This study indicates that in early posttransplant biopsies, fat, cholestasis, and ballooning can largely be attributed to PRI. By contrast, centrilobular hepatocyte loss should be suspected as a rejection related phenomenon, even if typical portal tract changes are not prominent, and augmentation of immunosuppression should be considered.


Subject(s)
Graft Rejection/pathology , Liver Circulation , Liver Transplantation , Liver/pathology , Preservation, Biological/adverse effects , Reperfusion Injury/pathology , Adolescent , Adult , Aged , Biopsy , Cholestasis/pathology , Cryopreservation , Fatty Liver/pathology , Female , Hepatocytes/pathology , Humans , Male , Middle Aged , Postoperative Period
16.
Hepatology ; 33(5): 1065-72, 2001 May.
Article in English | MEDLINE | ID: mdl-11343233

ABSTRACT

Mucosal addressin cell adhesion molecule (MAdCAM-1) plays a pivotal role in T-lymphocyte homing to the gut. Given the strong association between the autoimmune liver diseases primary sclerosing cholangitis and autoimmune hepatitis and inflammatory bowel disease, we investigated the role of MAdCAM-1 in recruiting mucosal lymphocytes to the liver. MAdCAM-1 was strongly expressed on inflamed portal vein/sinusoidal endothelium in autoimmune mediated liver disease. In modified Stamper-Woodruff assays, MAdCAM-1 on hepatic vessels supported adhesion of alpha4beta7+ lymphocytes (i.e., gut-derived T cells) from patients with inflammatory bowel disease and primary sclerosing cholangitis. This adhesion was inhibited by pretreatment with blocking antibodies to MAdCAM-1, alpha4beta7, or the integrin alpha4 chain indicating that MAdCAM-1 in inflamed liver is functionally active. Circulating lymphocytes from patients with primary sclerosing cholangitis showed rolling adhesion on MAdCAM-1 transfectants in a flow-based adhesion assay that could be blocked by anti-MAdCAM-1 or anti-alpha4beta7 mAbs. These findings indicate that, under certain circumstances, vessels in the human liver support adhesion of alpha4beta7+ mucosal lymphocytes via binding to aberrantly expressed MAdCAM-1 on liver endothelium. This provides a mechanism to explain the hepatic recruitment of mucosal lymphocytes in inflammatory liver disease complicating inflammatory bowel disease.


Subject(s)
Endothelium, Vascular/physiopathology , Hepatitis/physiopathology , Immunoglobulins/physiology , Intestinal Mucosa/physiopathology , Liver/physiopathology , Lymphocytes/physiology , Mucoproteins/physiology , Blood Cells/metabolism , Cell Adhesion/physiology , Cell Adhesion Molecules , Cholangitis, Sclerosing/pathology , Cholangitis, Sclerosing/physiopathology , Chronic Disease , Endothelium, Vascular/pathology , Humans , Inflammatory Bowel Diseases/pathology , Inflammatory Bowel Diseases/physiopathology , Integrins/metabolism , Intestinal Mucosa/pathology , Liver/pathology
17.
Liver Transpl ; 7(4): 285-91, 2001 Apr.
Article in English | MEDLINE | ID: mdl-11303286

ABSTRACT

Approximately 20% to 30% of patients undergoing liver transplantation for autoimmune hepatitis (AIH) develop features of recurrent disease. Diagnostic criteria for recurrent AIH are similar to those used in the nontransplanted liver and include, in varying combinations, biochemical, serological, and histological abnormalities and steroid dependency. However, these criteria are more difficult to apply in the liver allograft because of potential interactions between recurrent AIH and other complications of liver transplantation, particularly rejection, and the uncertain effects of long-term immunosuppression. In the absence of other reliable diagnostic markers, a number of studies have used the histological finding of chronic hepatitis as the main or sole criterion for diagnosing recurrent AIH. However, this also lacks diagnostic specificity because there are many other possible causes of chronic hepatitis in the liver allograft. In addition, approximately 20% to 40% of biopsies performed on patients as part of routine annual review have histological features of chronic hepatitis, for which no definite cause can be identified. Risk factors that have been associated with the development of recurrent AIH include suboptimal immunosuppression, HLA phenotype, disease type and severity in the native liver, and duration of follow up. In many cases in which recurrent AIH seems to be related to underimmunosuppression, biochemical and histological features rapidly resolve once adequate immunosuppression is restored. However, in other cases, recurrent AIH behaves more aggressively, with progression to cirrhosis and graft failure. Areas that require further study include developing uniform criteria for the diagnosis of recurrent AIH, identifying risk factors for severe recurrent disease, and determining optimal levels of immunosuppression that minimize the impact of disease recurrence without exposing patients to the risks of overimmunosuppression.


Subject(s)
Hepatitis, Autoimmune/etiology , Liver Transplantation , Postoperative Complications , Hepatitis, Autoimmune/diagnosis , Humans , Immunosuppression Therapy , Liver/pathology , Liver Transplantation/immunology , Recurrence , Risk Factors , Sensitivity and Specificity , Transplantation, Homologous
19.
J Hepatol ; 34(1): 4-10, 2001 Jan.
Article in English | MEDLINE | ID: mdl-11211906

ABSTRACT

BACKGROUND/AIMS: Lysyl fluorescein conjugated bile acid analogues (LFCBAA) closely parallel their natural counterparts. To assess LFCBAA as a tool for the visualization of bile acid transport within liver tissue. METHODS: Wistar rats were administered physiological concentrations of the primary bile acid analogue cholyllysyl fluoroscein (CLF) and of the secondary bile acid analogue lithocholyllysyl fluorescein (LLF) and serial liver biopsies were taken at fixed intervals. Both compounds were also injected retrogradely into the biliary tree. Frozen sections were examined by fluorescence microscopy. RESULTS: Both CLF and LLF were rapidly taken up from sinusoidal blood but differed significantly in their hepatic handling. CLF was rapidly transported into bile, whereas LLF transport was slower and produced significantly more bile duct fluorescence. LLF clearance showed a lobular gradient with last remaining bile acid being confined largely to zone 3. Both compounds were avidly taken up by cholangiocytes after injection intravenously or retrogradely into the biliary tree. CONCLUSIONS: Visualization of LFCBAA by fluorescence microscopy may yield further information regarding hepatobiliary bile acid localization during studies of physiological and pathological mechanisms involved in transport of bile acids. The presence of both compounds within cholangiocytes strongly suggests that they may undergo a degree of chole-hepatic recirculation.


Subject(s)
Cholic Acids/pharmacokinetics , Fluoresceins/pharmacokinetics , Fluorescent Dyes/pharmacokinetics , Lithocholic Acid/analogs & derivatives , Lithocholic Acid/pharmacokinetics , Liver/metabolism , Lysine/analogs & derivatives , Lysine/pharmacokinetics , Animals , Biological Transport , Biopsy , Male , Microscopy, Fluorescence , Rats , Rats, Wistar
20.
Arq Gastroenterol ; 38(4): 247-53, 2001.
Article in English | MEDLINE | ID: mdl-12068535

ABSTRACT

BACKGROUND: Non-alcoholic steatohepatitis was coined in 1980 to describe pathological and clinical features of non-alcoholic disease associated with pathological features, commonly seen in alcoholic-liver disease itself. It is now a well-recognised cause of end-stage liver disease and a rare cause of orthotopic liver transplantation. A small number of cases with recurrent non-alcoholic steatohepatitis following liver transplantation have been reported, however de novo non-alcoholic steatohepatitis in the liver allograft is not well recognised. AIMS/RESULTS: We report four cases of non-alcoholic steatohepatitis following orthotopic liver transplantation describing the factors related with the pathology. The recurrence of fatty infiltration occurred within 21 months and transition from mild steatosis to non-alcoholic steatohepatitis and early fibrosis was observed within 60 months post transplant in all four patients. All four cases had association with one or multiples risk factors (obesity, type 2 diabetes and/or hyperlipidemia). CONCLUSIONS: Management of this risk factors may play a therapeutic role in the prevention of recurrent and de novo non-alcoholic steatohepatitis following orthotopic liver transplantation.


Subject(s)
Fatty Liver/pathology , Liver Transplantation/pathology , Postoperative Complications/pathology , Aged , Biopsy , Diabetes Complications , Diabetes Mellitus/pathology , Fatty Liver/etiology , Female , Follow-Up Studies , Hepatitis/pathology , Humans , Male , Middle Aged , Obesity/complications , Recurrence , Risk Factors
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