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S G Hubscher

Publications and source records attributed to S G Hubscher.

At least 37 records · Page 2Linked to original sources
PubMed1998

Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis.

Alcoholic liver disease is associated with three histologically distinct processes: steatosis (parenchymal fat accumulation), alcoholic hepatitis (characterized by parenchymal infiltration by neutrophil polymorphs), and alcoholic cirrhosis (in which chronic inflammation and fibrosis dominate). Chemokines are cytokines that promote subset-specific leukoycte recruitment to tissues and could therefore play a crucial role in determining which leukocyte subsets are recruited to the liver in alcoholic liver disease. This paper reports that chemokine expression is increased in the liver of patients with alcoholic liver disease and, moreover, that distinct patterns of chemokine expression are associated with the different inflammatory responses to alcohol. Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were all detected in the parenchyma at sites of inflammation in alcoholic hepatitis, whereas in alcoholic cirrhosis, chemokines were restricted to inflammatory cells and endothelium in the fibrous septa and portal tracts. In alcoholic hepatitis, chemokine transcription was localized to sinusoidal cells, leukocytes, and fibroblasts in areas of parenchymal inflammation, but hepatocytes, despite staining strongly for chemokine protein, were negative. In alcoholic cirrhosis, chemokine mRNA was detected in portal tract endothelium, leukocytes, and fibroblasts. Thus, alcoholic hepatitis and alcoholic cirrhosis are associated with distinct patterns of chemokine expression that are likely to be important factors in determining whether a patient develops acute parenchymal inflammation and alcoholic hepatitis, or chronic septal inflammation and alcoholic cirrhosis.

Chemokine CCL2↗
PubMed1998

Immunolocalization of OV-6, a putative progenitor cell marker in human fetal and diseased pediatric liver.

The existence of progenitor (stem) cells in the human liver remains a matter of debate. In rodent models of hepatocarcinogenesis and injury, oval cells proliferate in the periportal regions of the portal tracts and are suggested to derive from a stem cell compartment, because they are capable of differentiating into hepatocytes or biliary epithelial cells. In this study, the rat oval cell marker, OV-6 has been used to investigate the hypothesis that there are stem cells present in fetal and pediatric human liver. The pattern of OV-6 expression was compared with the established adult biliary cell markers human epithelial antigen-125 (HEA-125) and cytokeratin-19 (CK-19). In normal pediatric liver (n = 7), bile ducts and ductules were immunostained with CK-19 and HEA-125, whereas OV-6 staining was consistently negative. In fetal tissue (n = 10), ductal plate cells, primitive bile ducts, and hepatoblasts were stained with CK-19 and HEA-125 although only some of the ductal plate cells and hepatoblasts were OV-6 positive. In biliary atresia (n = 6) and 1, anti-trypsin deficiency (1,AT) (n = 4), CK-19 and HEA-125 immunostained ductular proliferative cells that tended to form finely anastomosing ductules, whereas OV-6 staining was found more on discrete cells confined to portal tract margins. Additionally, in diseased liver, OV-6 was strongly positive in hepatocyte lobules with greatest intensity in the periseptal regions. This widespread hepatocyte OV-6 positivity suggests that the antibody may identify cells of a less differentiated phenotype (transitional hepatocytes) that have replaced the mature cells. Therefore, it is proposed that in human liver, OV-6 is recognizing cells with a progenitor stem cell-like phenotype with the capacity to differentiate into OV-6 positive ductular cells or lobular hepatocytes.

Adult↗
PubMed1998

Chronic hepatitis in children after liver transplantation: role of hepatitis C virus and hepatitis G virus infections.

BACKGROUND/AIMS: Chronic graft hepatitis occurs in 20-30% adults after liver transplantation but the prevalence and causes in children are not known. In adults, hepatitis C virus infection is prevalent prior to transplantation and recurrent infection is a frequent cause of graft dysfunction. The significance of the recently described hepatitis G virus infection remains unproven. The aim of this study was to examine the role of hepatitis C virus and hepatitis G virus infection in chronic graft hepatitis after paediatric liver transplantation. METHODS: The prevalence of graft hepatitis and the role of hepatitis C virus and hepatitis G virus infections in 80 children after liver transplantation have been studied, with a median follow up of 4.4 years (range 0.4 to 10.7), and the persistence of hepatitis G infection in the presence of immunosuppression has been determined. RESULTS: Chronic graft hepatitis was diagnosed in 19/80 (24%) children and was most frequently seen in children transplanted for cryptogenic cirrhosis (71%). There was no significant difference in the prevalence of chronic hepatitis in those transplanted before or after donor anti-HCV screening. Hepatitis C infection occurred in three children transplanted prior to donor screening but in only one was associated with chronic hepatitis. Hepatitis G infection was found in 22/79 (28%) transplant recipients but was not associated with graft hepatitis. In 17/21 children hepatitis G infection persisted for a median of 5.2 years after transplantation. CONCLUSION: Chronic hepatitis occurred in 24% of children after liver transplantation, a similar prevalence to that in adults. Cryptogenic liver disease predisposed to graft hepatitis, but neither hepatitis C nor hepatitis G infection was associated. Hepatitis G virus caused a frequent and usually persistent infection after transplantation.

Adolescent↗
PubMed1997

Posttransplantation chronic hepatitis in fulminant hepatic failure.

Non-A, non-B or seronegative hepatitis is the leading indication for liver transplantation in patients with fulminant hepatic failure (FHF). We examined protocol annual review liver allograft biopsy specimens in consecutive adult patients transplanted for FHF in an attempt to determine the extent of the histological changes. One hundred eleven biopsy specimens from 41 patients transplanted for fulminant seronegative hepatitis and 34 from a comparison group of 16 patients transplanted for other causes of FHF (11 paracetamol overdose, 2 idiosyncratic drug reaction, 3 Wilson's disease) were available. Specimens were analyzed using standard proforma without knowledge of the original diagnosis. Chronic hepatitis was present in 29 patients (71%) transplanted for fulminant seronegative hepatitis (23 mild, 3 moderate, and 3 severe) compared with 5 patients (31%, all mild) transplanted for other causes of FHF. Twenty-five patients (61%) grafted for seronegative FHF had fibrosis (13 mild, 9 moderate, and 3 severe) in contrast to 4 fibrosis (25%) (all mild) in the comparison group. Excluding early allograft failure because of primary graft nonfunction or vascular complications, six patients with seronegative FHF required retransplantation (2 = chronic rejection; 1 = severe hepatitis with panacinar necrosis, resembling original liver; and 3 = chronic hepatitis with precirrhotic fibrosis and prominent cholestasis of unknown cause). One patient in the comparison group had a second graft (chronic rejection). Posttransplantation chronic hepatitis is more frequent and severe in patients transplanted for seronegative hepatitis. Graft survival may be adversely influenced by the development of chronic hepatitis, which may represent persistent or recurrent disease.

Adolescent↗
PubMed1996

Expression of E-selectin and E-selectin ligands in human liver inflammation.

Lymphocyte recruitment to tissue is regulated by homing molecules expressed on subsets of leukocytes that bind to endothelial adhesion molecules termed addressins in target tissues. The addressins and homing molecules involved in recruiting lymphocytes to inflamed human liver are not known. E-selectin, which acts as an addressin for a subset of skin-infiltrating T cells that express a distinct E-selectin ligand called the cutaneous lymphocyte antigen (CLA), can be detected on endothelium in inflammatory liver diseases suggesting it might also act as an addressin for liver-infiltrating lymphocytes. To determine whether E-selectin does play such a role we looked for concomitant expression of E-selectin on hepatic endothelium and E-selectin ligands on infiltrating lymphocytes in liver sections from patients with primary biliary cirrhosis (PBC), acute allograft rejection, alcoholic liver disease, and normal liver. E-selectin was detected on vascular endothelium in association with lymphocytic infiltrates in all three liver diseases but not on normal endothelium. However, less that 10% of infiltrating lymphocytes expressed the only known lymphocyte E-selectin ligand, CLA. We used E-selectin chimeric fusion proteins to probe for novel E-selectin ligands on liver-infiltrating lymphocytes; however, less than 10% of lymphocytes had t he ability to bind the fusion proteins. Thus, E-selectin is unlikely to act as an addressin for liver-infiltrating lymphocytes, suggesting that other molecules are involved in lymphocyte recruitment to the liver. Despite the lack of binding to lymphocytes other structures in the liver expressed CLA and bound the E-selectin fusion proteins. Inflamed, but not normal, intrahepatic bile ducts expressed CLA and bound E-selectin, suggesting that they express activation dependent carbohydrate binding receptors. Furthermore, Kupffer cells did not express CLA but bound to both E-selectin fusion proteins, suggesting that they express potentially novel E-selectin ligands.

Antibodies, Monoclonal↗
PubMed1996

Recurrence of primary biliary cirrhosis in the liver allograft: the effect of immunosuppression.

BACKGROUND: Recurrence of primary biliary cirrhosis in the liver allograft remains controversial. METHODS: We have examined the liver allograft biopsies taken at 1 and 2 years after transplantation from patients receiving either FK506 or cyclosporin as part of a multi-centre trial. RESULTS: Histological features characteristic for primary biliary cirrhosis, including bile duct damage, ductopenia, bile duct proliferation and portal granulomas, were found more commonly and earlier after transplantation in patients receiving FK506 than cyclosporin. During the 2-year period, seven of 16 patients receiving FK506 and only one of 11 on cyclosporin had a graft biopsy suggestive of recurrent primary biliary cirrhosis. CONCLUSIONS: These findings confirm earlier reports that features of primary biliary cirrhosis recur in the liver allograft in some patients and suggest that the rate of recurrence may be affected by the immunosuppression regimen used.

Adult↗
PubMed1996

'Fragile' liver and massive hepatic haemorrhage due to hereditary amyloidosis.

The first case of amyloidosis is reported in which spontaneous massive hepatic haemorrhage necessitated emergency liver transplantation. Liver transplantation, as a treatment for a failing liver due to amyloidosis has not been previously reported. At transplantation, the liver tissue was uncharacteristically friable, although the subsequent vascular and biliary anastomoses were uncomplicated. Histological examination of the liver showed a surprisingly modest amount of amyloid, which was shown immunohistochemically to be derived from lysozyme, and a striking absence of reticulin staining. Both the patient's father and paternal grandfather had died from spontaneous hepatic haemorrhage, and histological review of their liver tissue showed similarly modest deposition of lysozyme-derived amyloid associated with loss of reticulin staining. In each case the quantity of amyloid was far less than would be expected to interfere with the mechanical integrity of the liver. This is the only report of hepatic disintegration associated with absence of reticulin staining, and it is probable that the mechanism represents a novel secondary effect of the amyloid deposits in the livers of this family.

Adolescent↗
PubMed1996

Accuracy of staging in primary biliary cirrhosis.

AIMS: To evaluate sampling variability of liver biopsy in patients with primary biliary cirrhosis (PBC). METHODS: Sections from 50 PBC liver specimens obtained at transplantation were examined. The degree of fibrosis was assessed on a scale of 0-4 using two methods: (1) simulated needle biopsy in fields approximately the size of conventional needle biopsy; and (2) whole section scanning in areas with little and extensive fibrosis. RESULTS: Considerable variation in the range of stages of fibrosis was found when the whole section scanning method was used. Only 10 (20%) samples had a consistent degree of fibrosis in all sections scanned. By contrast, the same fibrosis stage was assigned in 30 (60%) specimens examined using the simulated needle biopsy method. When the results obtained by the two methods were compared, there was a discrepancy of one or two stages in 32 samples. This discrepancy was the result of discovering areas with a lesser degree of fibrosis in whole sections compared with the simulated needle biopsy specimens. CONCLUSION: There is considerable variation in the degree of fibrosis in the livers of patients with PBC, even when end stage specimens obtained at transplantation are examined. Consistent results were obtained when simulated needle biopsy specimens were examined. This, however, may be a reflection of the procedure applied when staging liver needle biopsy specimens, where the greatest degree of abnormality is used in determining the stage. The practice of staging of PBC in small needle biopsy specimens is valuable as long as the appearances are interpreted with caution, bearing in mind that there is considerable variability in the degree of fibrosis.

Adult↗
PubMed1995

Timing, significance, and prognosis of late acute liver allograft rejection.

Liver allograft rejection is usually divided into acute (cellular) rejection and chronic (ductopenic) rejection. Most cases of acute rejection occur within four weeks of transplantation. There is a paucity of published literature on late acute rejection (LAR) in liver allografts and little is known about factors affecting its occurrence and outcome. To study the predisposing factors, clinical presentation, and prognosis of LAR, data prospectively collected on consecutive adult patients who underwent liver transplantation between 1982 and 1994, were analyzed. LAR was defined as histologically confirmed acute cellular rejection occurring 30 or more days after liver transplantation. Of the 717 patients, 59 (7.5%) had 71 episodes of LAR. Fifty-seven episodes were seen during the first year after transplantation, the remaining occurring between 1 and 6 years. Age, sex, pretransplant diagnosis, donor match of HLA, and blood groups was not associated with risk of LAR. Twenty-seven (38%) episodes were preceded by subtherapeutic blood levels of cyclosporine/FK506 (< 100 ng/ml and < 5 ng/ml, respectively) while an additional 6 (8%) had marginally low blood levels (< 150 ng/ml and < 10 ng/ml, respectively). Treatment with high-dose prednisolone resulted in complete resolution of rejection in 36 (51%) episodes, partial response in 21, and no response in 14 patients. Sixteen patients (27%) developed chronic rejection and graft loss. Development of chronic rejection was not affected by age or sex of the patient, timing of LAR, or histological severity of AR. Delayed response to therapy during an earlier episode of AR, and histological findings of centrilobular necrosis or bile duct loss at the time of diagnosis of LAR were associated with high risk of progression to chronic rejection and graft loss.

Adolescent↗
PubMed1995

Hepatitis C virus infection in the asymptomatic British blood donor.

Blood donor screening for hepatitis C virus (HCV) antibodies is now routine. Most blood transfusion services recommend that seropositive donors are referred for further investigation. Southern European studies suggest that many asymptomatic seropositive donors have clinically significant liver disease. Seropositive donors in areas of high prevalence may not, however, be representative of British donors. We have prospectively examined the prevalence and severity of HCV infection in a British volunteer blood donor population. During a 14 month period, only 0.35% (999/287,332) of all donors in the West Midlands were anti-HCV (screening assay) positive. Only 5% (52/999) of these were confirmed true seropositive. Nearly 80% (41/52) of seropositive donors were referred to the Queen Elizabeth Hospital Liver Unit for further investigation. Most underwent complete investigation, including liver biopsy. Forty of forty-one donors had biochemical, histological, or virological evidence of persistent viral infection. Histological changes were generally mild and none was cirrhotic. Covertly infected patients had less severe disease than those with an overt risk factor for HCV exposure. In the British Midlands, the prevalence of blood donor seropositivity is low. In contrast with seropositive Southern European donors, the British donor is more likely to belong to an at-risk group for parenteral exposure and is less likely to have severe histological changes. This study highlights the importance of developing locally relevant guidelines for the counselling and investigation of anti-HCV-positive blood donors.

Adult↗
PubMed1995

Stathmin is expressed by the proliferating hepatocytes during liver regeneration.

Aim-To determine the liver cell populations that express the phylogenetically conserved cytosolic protein stathmin during liver regeneration.Methods-Double immunostaining for stathmin and the Ki67 antigen was performed on sections of formaldehyde fixed, paraffin wax embedded tissues from 31 liver specimens. These included a variety of disease conditions characterised by some degree of hepatocyte regeneration. Quantitative western blot analysis was performed on 22 of these specimens.Results-Variable amounts of stathmin protein were detected by western blotting in all of the specimens examined. Stathmin was not detected in three cases of histologically normal liver. On immunostaining, stathmin was demonstrated in a proportion of hepatocytes as well as lymphoid inflammatory cells and other tissue elements. In all cases most of these stathmin positive cells showed nuclear positivity for the Ki67 antigen.Conclusions-Stathmin is expressed by proliferating hepatocytes but not by resting hepatocytes. Thus, it is likely that the protein has a function important to cell proliferation as opposed to cell differentiation.

Journal Article↗
PubMed1994

Hepatocyte growth factor and macrophage inflammatory protein 1 beta: structurally distinct cytokines that induce rapid cytoskeletal changes and subset-preferential migration in T cells.

T-cell migration into tissue depends on a cascade of rapid and selective adhesive interactions with endothelium. "Triggering" is a step in that cascade required to activate T-cell integrins. Hepatocyte growth factor (HGF) may be a physiologically relevant trigger, since we demonstrate that HGF can induce both adhesion and migration of human T-cell subsets and can be detected immunohistochemically on inflamed endothelium. HGF preferentially induces responses from T cells of memory phenotype, in contrast to macrophage inflammatory protein 1 beta (MIP-1 beta), a chemokine which acts preferentially on naive cells. HGF, like the chemokines, binds to heparin, and HGF retained in extracellular matrix is efficient in promoting migration. Further, both MIP-1 beta and HGF induce actin polymerization within seconds, kinetics that approach those required to contribute to physiologic triggering. HGF is a member of a structural family distinct from the chemokines, whose only known receptor is the tyrosine kinase c-Met. HGF induces tyrosine phosphorylation on T cells apparently via a distinct receptor, since no c-Met is detectable by surface staining, PCR, or anti-phosphotyrosine immunoprecipitation. Thus, promotion of T-cell adhesion and migration are previously undescribed functions of HGF that we propose are relevant to selective T-cell recruitment.

Cell Adhesion↗