Biomedical subjects
Publications and source records attributed to Stefan G Hubscher.
Malignant infiltration of the liver is a rare cause of acute liver failure accounting for less than 1% of cases. We describe a case of adult T-cell leukemia (ATL) that presented with a prodromal illness that progressed to jaundice, hepatic encephalopathy, multisystem failure and death within 8 weeks. Liver histology revealed massive infiltration with atypical lymphocytes typical of ATL and liver necrosis.
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Carcinosarcoma of the biliary tract is extremely rare. Little is known about the natural course of these tumours, or the best available treatment. We present two cases of carcinosarcoma of the biliary tract, one of the gall bladder and one of the common bile duct, followed by a review of the literature.
The clinical outcome of patients who have undergone liver transplantation for hereditary hemochromatosis (HH) or who have received iron-loaded donor grafts is unclear. We reviewed 3,600 adult primary orthotopic liver transplants and assessed the outcomes in 22 patients with HH. We also evaluated graft function and iron mobilization in 12 recipients of iron-loaded donor grafts. All 22 subjects who received liver transplants for HH were male; 13 had other risk factors for liver disease. HH patients had comparatively poor outcomes following transplantation: survival at 1, 3, and 5 years posttransplantation were 72%, 62%, and 55%, respectively. Recurrent hepatocellular cancer was the most common cause of death. There was no convincing evidence of reaccumulation of iron in the grafted liver in HH; however, 1 subject demonstrated increased serum ferritin concentration and grade 2 hepatic siderosis. Liver iron stores were slow to mobilize in 7 of the 12 recipients of iron-loaded grafts. These recipients had appropriate early graft function, but 2 patients with heavy iron loading and increased hepatic iron developed hepatic fibrosis. In conclusion, (1) HH is an uncommon indication for liver transplantation, and the majority of patients requiring transplantation had other risk factors for chronic liver disease; (2) reaccumulation of liver iron in HH patients is very unusual, but increased iron stores may be slow to mobilize in normal recipients of iron-loaded grafts, potentially compromising late graft function; (3) post-liver transplant survival is reduced in HH, and affected patients require careful clinical evaluation of perioperative and postoperative risk factors. Our data suggest that iron excess in HH does not wholly depend on intestinal iron absorption but is also influenced by liver factors that moderate iron metabolism.
Mutations in the Jagged1 gene, a ligand for the Notch signalling pathway, have been implicated in the pathogenesis of Alagille syndrome (AGS), resulting in bile duct paucity. Recently, a mouse model for AGS suggested that abnormalities of the Notch2 receptor, as well as of Jagged1, may be present. Expression patterns of Notch receptors have not been described in the developing human liver or in paediatric liver. The expression of Notch receptors and ligands was examined in fetal, paediatric normal, and diseased human liver by RT-PCR and immunohistochemistry. RT-PCR showed Notch1-4 mRNA expression to be present. In fetal liver, Notch3 protein was expressed on mesenchymal cells, closely adjacent to ductal plate cells that expressed Jagged1. In paediatric normal liver, Notch1 and Notch2 were present on mature bile duct cells. Notch expression was altered in disease, with distinct differences in AGS from extrahepatic biliary atresia (EHBA) and alpha1-anti-trypsin deficiency (alpha1AT). In AGS, where extensive ductular reaction was present, Jagged1 was expressed on ductular reactive cells (DRCs), along with marked Notch2 and Notch3 staining. Where there was ductular paucity, Notch2 and Notch3 were not expressed on remaining biliary epithelial cells. In EHBA and alpha1AT, Notch receptor expression was not seen on DRCs. Instead, Notch2 and Notch3 were expressed by stromal cells. In all diseases, Notch3 was expressed on neovessels in portal tracts and cirrhotic fibrous septa. In conclusion, Notch3 is expressed in close proximity to Jagged1 at the time of ductal plate formation, suggesting that Notch3 is important for bile duct development. The expression of both Notch2 and Notch3 in AGS on DRCs confirms that these receptors may be important in the pathogenesis of this disease. Further studies are required to investigate the presence of Notch2 and Notch3 at other periods in liver development and to clarify the role of Notch signalling in paediatric cholestases.
OBJECTIVE: Preliminary reports suggest that patients with primary biliary cirrhosis (PBC) have evidence of human betaretrovirus infection. The aim of this study was to determine whether antiviral therapy impacts on the disease process. METHODS: We conducted two consecutive open-labeled, nonrandomized, 1-yr pilot studies; the first with lamivudine 150 mg/day and the second with Combivir combination therapy using lamivudine 150 mg and zidovudine 300 mg twice a day. Eleven PBC patients enrolled in each study, seven patients were entered into both studies, and one patient was withdrawn from each study due to side effects. RESULTS: Evaluation of liver biopsies before and after lamivudine therapy showed a 4-5 increase in necroinflammatory score, a 1-1.5 elevation in bile duct injury, with little change in the percentage of portal tracts with bile ducts (50-52%). None of the patients in the lamivudine study normalized alkaline phosphatase. Histological assessment following Combivir therapy revealed a 6 to 4 improvement in necroinflammatory score (p < 0.03, 95% CI: 0.53-2.33), a 3 to 1 reduction in bile duct injury (p < 0.02, 95% CI: 1.08-2.07), and a 45-75% increase in portal tracts with bile ducts (p < 0.05, 95% CI: 0.02-0.29). In the Combivir cohort, five patients normalized alkaline phosphatase and four developed normal AST, ALT, and alkaline phosphatase. CONCLUSIONS: Histological and biochemical endpoints were achieved in the Combivir pilot study suggesting a larger placebo-controlled trial is required as a proof of principle to assess whether antiviral therapy impacts the PBC disease process.
The Epstein-Barr virus (EBV) has recently been associated with hepatocellular carcinoma (HCC) arising in Japanese patients. We analyzed 82 cases of HCC from Germany and the U.K. for the presence of EBV DNA and viral gene products within tumor cells. Initial screening of whole sections using quantitative (Q)-PCR detected EBV DNA in 9/58 U.K. cases and in 9/24 German cases; in positive cases viral load was very low, ranging between 1.4 and 49.1 copies of the EBV genome/1000 cell equivalents, compared to much higher values for EBV-positive Hodgkin's disease and nasopharyngeal carcinoma controls (range, 714-3259/1000 cells). EBV DNA was not detected in the tumor cells of any of the Q-PCR-positive cases either by Q-PCR of pure tumor cell populations isolated by laser capture microdissection or by isotopic in situ hybridization. Furthermore, none of the German or U.K. HCC tumors tested positive for EBER or EBNAI expression in tumor cells. Our results provide strong evidence that HCCs from the U.K. or Germany are not associated with EBV.
The search for human oval cells or bi-potential stem cells in the human liver is the subject of intensive investigation. Fetal hepatocytes (hepatoblasts) have some proliferative and bipotential capacity, but access to sufficient numbers of cells remains limiting. Candidate stem cells in the adult normal and diseased human liver have been identified using markers such as OV6, CD34, c-kit and NCAM. Lack of stem cell marker specificity however, remains a problem and further, more specific markers are required. The molecular signaling molecules and transcription factors that control proliferation and cell differentiation pathways into hepatocyte or biliary phenotype are beginning to emerge. However, whether any of the current liver stem cell approaches will be converted into effective clinical cell transplantation or gene therapy treatments has yet to be proven.
BACKGROUND: Gastric zygomycosis is a rare but potentially lethal complication in transplant patients. Forty-two cases of gastric mucormycosis have been described in the literature, with a mortality of 98%. METHODS: We report of a case of gastric mucormycosis in a 45-year-old male undergoing liver transplantation for alcohol-induced cirrhosis. The diagnosis was made 20 days after transplantation in a biopsy of a bleeding gastric ulcer identified during a reoperation for a common bile duct stricture. RESULTS: After the surgical procedure and therapy with amphotericin B, the patient made a good recovery and is alive and well 2 years after transplantation. CONCLUSIONS: Gastric mucormycosis should be suspected in those patients in whom gastrointestinal symptoms such a pain or bleeding are present. Because the diagnosis is dependent on histology, the importance of biopsy cannot be underestimated. Once diagnosed, a successful outcome depends on effective treatment with amphotericin.
The Jagged and Delta family of transmembrane proteins are ligands for Notch receptors, which control the proliferation and/or differentiation of many cell lineages. Expression and localization of these ligands in the adult human liver has not been fully elucidated, nor whether dysregulation of these proteins contributes to liver disease processes. We have examined expression of the five known Notch ligands in human liver. Expression of Jagged-1 and Delta-4 mRNA was seen in normal and diseased liver tissue, whereas Jagged-2, Delta-1, and Delta-3 mRNA was undetectable. In primary liver cell isolates, Jagged-1 expression was found in all cell types, whereas Delta-4 was present in biliary epithelial and liver endothelial cells, but absent in hepatocytes. Interestingly, Jagged-1 mRNA expression was significantly up-regulated in diseased liver tissue. By immunohistochemistry, Jagged-1 expression was present on most structures in normal tissue. However in disease, strikingly strong Jagged-1 immunoreactivity was observed on many small neovessels and bile ductules. The expression of downstream modulators and effectors of Notch signaling was also detectable in purified cell isolates. This, together with aberrant Jagged-1 expression suggests that the Notch signaling pathway may play a role in the neovascularization and biliary defects observed in the liver during the development of cirrhosis.
The normal liver contains a large number of lymphocytes, which include not only specialized natural killer (NK) and NKT cells but also CD4 and CD8 T cells. Whereas some of these cells are terminally differentiated effector cells that are destined to die by apoptosis, many of them are not and include immunocompetent cells that traffic through the liver to provide continuing immune surveillance as well as epithelial-associated effector T cells. In alcoholic liver disease the number of lymphocytes in the liver increases and the type and distribution of these infiltrating cells will determine the nature of the inflammation. For instance, a predominance of parenchymal inflammation is a feature of alcoholic hepatitis, whereas a predominantly portal infiltrate is a feature of cirrhosis. In this article we discuss the molecular mechanisms that regulate the entry of lymphocytes to the inflamed liver in alcoholic hepatitis. Lymphocytes play a critical role in regulating the immune/inflammatory response to alcohol, and understanding how these cells are recruited to the liver has important implications for understanding the pathogenesis of alcoholic liver disease in which parenchymal infiltration is a critical determinant of disease progression. Aberrant recruitment and retention of lymphocytes in the liver may explain why some patients with alcoholic liver disease show progressive inflammatory damage whereas in others the disease takes a more indolent course. Similarly, leukocyte recruitment may present new therapeutic targets in which lymphocyte recruitment to the specific liver compartments can be inhibited, thereby minimizing tissue damage whilst leaving generalized lymphocyte recirculation intact. Potentially the most exciting potential is to modulate the nature of the lymphocyte subsets recruited to the liver, so that harmful cells are excluded and beneficial subsets are preferentially recruited.
Criteria for histologic diagnosis of chronic rejection (CR) are based on changes seen late in the disease process that are likely to be irreversible and unresponsive to treatment. Changes occurring during the evolution of CR are less clearly defined. The serial biopsy specimens, failed allografts, and biochemical profiles of 28 patients who underwent retransplantation for CR were examined with the aim of identifying histologic and biochemical features that were present during the early stages of CR. For each case, a point of acute deterioration in liver function tests (LFTs) was identified ("start time" [ST]) that subsequently progressed to graft failure. Biopsy specimens before, at the time of ("start biopsy" [SB]), and after the ST were assessed histologically, and findings were correlated with the biochemical changes. CR resulted from acute rejection (AR) that did not resolve. Centrilobular necroinflammation (CLNI) associated with an elevated aspartate transaminase (AST) level and portal tract features of AR were present at the start. Portal AR features resolved, CLNI persisted, AST level remained elevated, and bilirubin and alkaline phosphatase levels progressively increased throughout the evolution of CR. Portal tracts also showed a loss of small arterial and bile duct branches, with arterial loss occurring early and bile duct loss as a later progressive lesion. Foam cell arteriopathy was rarely seen in needle biopsy specimens. In conclusion, findings from this study may help identify patients at risk of progressing to graft loss from CR at a stage when the disease process is potentially reversible and amenable to treatment.