Hepatitis: Hübscher SG

Hübscher SG. · No affiliation provided · Liver Transpl. · Pubmed #18433067 links to  free full text

This publication has no abstract.

Hübscher SG. · Department of Pathology, University of Birmingham, Birmingham, UK. · Semin Liver Dis. · Pubmed #19235661 No free full text.

Abstract: This article focuses on the main patterns of damage that are seen in liver allograft biopsies. As with the interpretation of liver biopsies from the native liver, clinicopathological correlation is very important. The therapeutic implications of the biopsy report should also be considered, in particular whether changes in immunosuppression are indicated. For some conditions, such as liver allograft rejection, histology remains the gold standard for diagnosis. In other cases, a likely cause of graft dysfunction may already have been identified by other methods, but liver biopsy still provides useful additional information (e.g., assessing disease severity in hepatitis C infection) and may identify an additional or alternative cause for graft dysfunction (e.g., coexistent metabolic fatty liver disease). In cases where there is a dual pathology, liver biopsy may also help to identify the predominant cause of graft damage.

Schreuder TC, Hübscher SG, Neuberger J. · Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK. · Transpl Int. · Pubmed #18662365 No free full text.

Abstract: Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) may all recur after liver transplant. Diagnosis of rPBC is defined by histology; rAIH by serology, biochemistry and histology; rPSC by histology and/or imaging of the biliary tree and exclusion of other causes of nonanastomotic biliary strictures. Criteria for recurrent disease (RD) may differ from those used in similar disease in the native liver: frequent use of immunosuppressive therapy changes the pattern and natural history of RD and can co-exist with other transplant-related causes of graft damage. RD may occur in the presence of normal liver tests; the reported incidence will depend on the way in which diagnostic tests (especially protocol biopsies) are applied. The risk of RD increases with time, but does not correlate with the rate of graft loss. Treatment is largely unproven: ursodeoxycholic acid will improve serology and may slow progression of rPSC and rPBC; introduction or increased dose of corticosteroids may reduce progression of rAIH. Risk factors for rPBC include use of tacrolimus compared with cyclosporine; for rPSC include absence of colon peri-transplantation and for rAIH possible associations with some HLA haplotypes have been suggested.

Hübscher SG. · Department of Pathology, University of Birmingham, Birmingham, United Kingdom. · Semin Diagn Pathol. · Pubmed #17355090 No free full text.

Abstract: Histological assessments continue to have an important role in the diagnosis and management of graft complications following liver transplantation. For some conditions, such as liver allograft rejection, histology is regarded as the "gold standard" for diagnosis. In other cases, where a likely cause of graft dysfunction has been identified using other methods, liver biopsy provides important additional information (e.g., severity of necroinflammatory activity and fibrosis in recurrent hepatitis C infection) and may point to the presence of an additional or alternative cause for graft dysfunction. In cases where a dual pathology is suspected (eg, hepatitis C and rejection), histological findings can help to identify the main cause of graft dysfunction. This article will focus on the main patterns of damage that are seen in post-transplant liver biopsies and their differential diagnosis. As with the assessment of liver biopsies in the native liver, clinico-pathological correlation is very important. Consideration should also be given to the therapeutic implications of the biopsy report, in particular whether changes in immunosuppression are indicated.

Hübscher SG. · Department of Pathology, University of Birmingham, Birmingham, UK. · Histopathology. · Pubmed #17064291 No free full text.

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.

Hübscher SG. · Department of Pathology, University of Birmingham, UK. · Eur J Gastroenterol Hepatol. · Pubmed #15489567 No free full text.

Abstract: Assessments of liver biopsies are important in the diagnosis and management of non-alcoholic fatty liver disease. Histology remains the 'gold standard' for making the important distinction between simple steatosis, which is generally non-progressive and readily reversible, and steatohepatitis, which has the potential to progress to severe fibrosis or cirrhosis. Liver biopsy may also identify other causes of liver disease in patients thought to have fatty liver disease and vice versa. Histological grading and staging of fatty liver disease require further study but these are potentially important approaches for studying disease severity and progression, particularly in the context of clinical trials to assess novel therapeutic approaches.

Hübscher SG. · Department of Pathology, University of Birmingham, Birmingham, UK. · Liver Transpl. · Pubmed #11303286 links to  free full text

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.

Reynolds GM, Harris HJ, Jennings A, Hu K, Grove J, Lalor PF, Adams DH, Balfe P, Hübscher SG, McKeating JA. · Liver Laboratories, Institute for Biomedical Research, University of Birmingham and University Hospital Birmingham NHS Foundation Trust, Birmingham, United Kingdom. · Hepatology. · Pubmed #18085708 No free full text.

Abstract: The principal site of hepatitis C virus (HCV) replication is the liver. HCV pseudoparticles infect human liver derived cell lines and this suggests that liver-specific receptors contribute to defining HCV hepatotropism. At least three host cell molecules have been reported to be important for HCV entry: the tetraspanin CD81, scavenger receptor class B member I (SR-BI), and the tight junction (TJ) protein Claudin 1 (CLDN1). Hepatocytes in liver tissue coexpress CD81, SR-BI, and CLDN1, consistent with their ability to support HCV entry. CLDN1 localized at the apical-canalicular TJ region and at basolateral-sinusoidal hepatocyte surfaces in normal tissue and colocalized with CD81 at both sites. In contrast, CLDN1 appeared to colocalize with SR-BI at the basolateral-sinusoidal surface. CLDN1 expression was increased on basolateral hepatocyte membranes in HCV-infected and other chronically inflamed liver tissue compared with normal liver. In contrast, CLDN4 hepatocellular staining was comparable in normal and diseased liver tissue. CONCLUSION: HCV infection of Huh-7.5 hepatoma cells in vitro significantly increased CLDN1 expression levels, consistent with a direct modulation of CLDN1 by virus infection. In HCV infected livers, immunohistochemical studies revealed focal patterns of CLDN1 staining, suggesting localized areas of increased CLDN1 expression in vivo which may potentiate local viral spread within the liver.

Seyam M, Neuberger JM, Gunson BK, Hübscher SG. · Liver Unit, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK. · Liver Transpl. · Pubmed #17370332 links to  free full text

Abstract: Liver allograft cirrhosis is a relatively uncommon complication of liver transplantation. Most cases can be attributed to disease recurrence, particularly recurrent hepatitis C. Little is known about the frequency, etiology, and natural history of liver allograft cirrhosis occurring without evidence of recurrent disease. The aim of the present study was to review the clinicopathological features in this group of patients. We retrospectively reviewed data from all adult patients who were transplanted between 1982 and 2002 and survived >12 months after orthotopic liver transplantation (n = 1,287). Cases of histologically proven cirrhosis were identified from histopathological data entered into the Liver Unit Database. A total of 48 patients (3.7%) developed cirrhosis. In 29 of them, cirrhosis could be attributed to recurrent disease (hepatitis C, 11; hepatitis B, 4; autoimmune hepatitis, 4; primary biliary cirrhosis, 2; primary sclerosing cholangitis, 3; nonalcoholic steatohepatitis, 4; alcoholic liver disease, 1). In 9 of the 19 patients without evidence of disease recurrence, another cause of cirrhosis could be identified (de novo autoimmune hepatitis, 4; biliary complications, 4; acquired hepatitis B, 1). In the remaining 10 cases, the cause of cirrhosis remained unknown; their previous biopsies had shown features of chronic hepatitis of uncertain etiology. Three patients in this group died, and the remaining 7 are alive with good graft function 3-12 years after cirrhosis was first diagnosed. The prevalence of "cryptogenic" posttransplant cirrhosis was significantly higher in patients initially transplanted for fulminant seronegative hepatitis (6%) than in those transplanted for other diseases (0.3%). In conclusion, posttransplant cirrhosis without disease recurrence is uncommon, but it is more frequent in patients transplanted for fulminant seronegative hepatitis. Chronic hepatitis is the most frequent underlying pathological process in cases where the cause of cirrhosis remains uncertain.

Heydtmann M, Lalor PF, Eksteen JA, Hübscher SG, Briskin M, Adams DH. · Birmingham University, Edgbaston, United Kingdom. · J Immunol. · Pubmed #15634930 links to  free full text

Abstract: Lymphocyte recruitment to the liver is critical for viral clearance in acute hepatitis and in the pathogenesis of chronic inflammatory liver disease when persistent chronic inflammation leads to fibrosis and cirrhosis. Chemokines regulate leukocyte recruitment and positioning in tissues and are thus critical regulators of chronic inflammation. The chemokine CXCL16, which is found in liver tissue, exists in a transmembrane as well as soluble form, providing a potential mechanism for localization to particular structures. We studied the role of CXCL16 and its receptor CXCR6 in lymphocyte recruitment and retention in the liver. A higher proportion of CXCR6(+) T cells was detected in blood of hepatitis C virus patients compared with healthy subjects, and in chronic inflammatory liver disease >60% of intrahepatic T cells expressed CXCR6, including CD4, CD8, and CD56(+) T cells compared with <30% in matched blood samples. CXCR6(+) lymphocytes were found in association with CXCL16(+) bile ducts in portal tracts and with hepatocytes at sites of interface hepatitis. Analysis of CXCL16 expression and subcellular distribution in cultured human cholangiocytes, sinusoidal endothelial cells, and hepatocytes revealed that all three cell types expressed CXCL16, with the strongest staining seen on cholangiocytes. CXCL16 on the cholangiocyte membrane was able to support lymphocyte adhesion by triggering conformational activation of beta(1) integrins and binding to VCAM-1. Thus, CXCL16 can promote lymphocyte adhesion to epithelial cells and may function to attract and retain effector cells that promote biliary and hepatocyte destruction in inflammatory liver disease.

Garcia RF, Morales E, Garcia CE, Saksena S, Hübscher SG, Elias E. · Liver Unit, Queen Elizabeth Hospital, Birmingham, B15 2TH, UK. · Arq Gastroenterol. · Pubmed #12068535 No free full text.

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.

Grant AJ, Lalor PF, Hübscher SG, Briskin M, Adams DH. · MRC Centre for Immune Regulation, Liver Research Laboratories, Queen Elizabeth Hospital, Birmingham, UK. · Hepatology. · Pubmed #11343233 No free full text.

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.