Intraocular lymphoma after liver transplantation.
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Eye Neoplasms↗
Biomedical subjects
J M Neuberger
Publications and source records attributed to J M Neuberger.
Primary biliary cirrhosis. Histological evidence of disease recurrence after liver transplantation.
Histological evidence of primary biliary cirrhosis (PBC) recurring after orthotopic liver transplantation (OLT) was looked for in a 'blinded' study of 353 biopsies from 188 patients, 12-100 months post-transplant. Biopsies (172) were obtained from 83 patients transplanted for PBC and 181 biopsies from 105 patients with other liver diseases. Sixteen biopsies from 13 PBC patients (16%) had features suggestive of recurrent disease. The main diagnostic findings were: mononuclear portal inflammatory infiltration (n = 16), portal lymphoid aggregates (n = 14), portal epithelioid granulomas (n = 14) and bile duct damage (n = 15). This combination of changes was not seen in any biopsy from the non-PBC group. Additional features supporting a diagnosis of recurrent disease were ductopenia (n = 7), bile ductular proliferation (n = 7), portal fibrosis (n = 6) and copper deposition (n = 5). Thirteen biopsies from 12 patients were classified as stage I or II histologically. The other patient developed progressive damage in three serial biopsies resulting in an early micronodular cirrhosis, 5 years post-transplant. These observations provide further evidence that PBC recurs after OLT. More studies are required to determine the natural history and clinical significance of the predominantly early histological changes documented so far.
Adolescent↗
Managing severe alcoholic hepatitis complicated by renal failure.
We examined the management and outcome of 15 patients admitted consecutively to a specialist Liver Unit with severe alcoholic hepatitis complicated by renal failure. Fourteen patients were managed conservatively. Of these, 11/14 underwent renal dialysis for a mean of 24 days. Three patients, including two requiring dialysis, recovered renal function. Despite intensive care, 12/14 patients died. Death was frequently associated with bacterial and fungal sepsis. One patient underwent liver transplantation with prompt post-operative recovery of renal function. He was discharged from hospital 16 days later, and remains abstinent from alcohol with normal liver function after one year. Most patients with renal failure complicating severe alcoholic hepatitis will die, despite intensive care including renal dialysis. Selected patients may be suitable for liver transplantation.
Adult↗
Detection of circulating intercellular adhesion molecule-1 after liver transplantation--evidence of local release within the liver during graft rejection.
The adhesion molecule ICAM-1 mediates leucocyte adhesion to target structures and other immune cells by binding with the leucocyte adhesion receptors LFA-1 and MAC-1. During rejection of human liver transplants there is increased expression of ICAM-1 on target structures such as bile ducts and venous endothelium and also on lymphocytes infiltrating the graft. Recent reports suggest that a soluble, functionally active form of ICAM-1 designated circulating ICAM-1 (cICAM-1) is released by activated lymphocytes and might be an important mechanism for modulating lymphocyte adhesion and the inflammatory process. We detected cICAM-1 in bile and serum after liver transplantation using an enzyme-linked immunosorbent assay. Serum cICAM-1 was elevated early in the course of acute rejection and appeared at the same time as the soluble interleukin-2 receptor, a marker of lymphocyte activation. Serum levels, however, were not specific for rejection since they were also elevated in infective complications. In contradistinction, biliary levels of cICAM-1 were only elevated in rejection and appeared to be due to local release/secretion within the liver. These data demonstrate that cICAM-1 is released within the liver during graft rejection, probably from activated lymphocytes, and support previous studies that suggested that factors in bile reflect immunological activity within the liver graft more closely than serum factors.
Bile↗
Acute liver allograft rejection--is treatment always necessary?
A group of 195 consecutive adult patients who received a primary orthotopic liver allograft were reviewed retrospectively to analyze the incidence of rejection, the response to antirejection therapy, and the impact of acute rejection on the development of ductopenic rejection. The diagnosis of acute rejection (AR) was based on a combination of clinical and histological criteria, and 69.7% of the patients had at least one episode of acute rejection. Only 6.7% of the patients failed to respond to steroids and were treated with OKT3. Four (2.3%) patients developed acute vanishing bile duct syndrome (within 60 days) and 6 (3.5%) patients developed chronic rejection. Eight patients who spontaneously recovered from AR without additional immunosuppression are described in detail. In addition to histological damage, all developed significant hepatic dysfunction. Except for one patient who died from disseminated fungal infection, the 7 remaining patients are alive with excellent graft function 7 to 21 months posttransplant. While severe AR and recurrent AR should be treated without delay, some patients with mild-to-moderate rejection and hepatic dysfunction may resolve without additional immunosuppression.
Acute Disease↗
Steroid withdrawal from long-term immunosuppression in liver allograft recipients.
Corticosteroids were withdrawn from the immunosuppressive regimen of 168/197 (85%) of liver transplant patients who survived for more than three months. In 14, steroids were restarted for reasons other than rejection. The remaining 154 patients were evaluated for the occurrence of rejection and graft loss. Risk factors for the development of rejection after steroid withdrawal were assessed. There were 13 episodes of rejection in 12 (7.8%) grafts; 7 (4.5%) experienced acute cellular rejection, and 6 (3.9%) developed chronic ductopenic rejection. All cases of acute rejection resolved with high-dose steroids. Graft and patient loss due to chronic rejection was 3 (1.9%) and 2 (1.3%), respectively. Chronic rejection resolved in 1 patient, 1 was successfully retransplanted, and in the other 2 the principal cause of death was recurrent tumor. None of the risk factors examined (primary indication for transplant, severity of previous acute rejection, use of OKT3, retransplantation, ABO blood group donor/recipient match, CMV infection, and CsA mono versus CsA and AZA double therapy) were associated with the development of chronic rejection poststeroid withdrawal. The prevalence of side effects, after steroid withdrawal, was low; 66% of patients never required antihypertensive medication; 14% experienced a significant septic episode, and only 4 died with sepsis as the major factor. There were no fungal sepsis and no new cases of diabetes. Withdrawal of corticosteroids after 3 months can be successfully achieved in the majority of liver allograft recipients and is associated with a low rate of rejection, graft loss, and complications attributable to immunosuppressive medication.
Adolescent↗
Intercellular adhesion molecule-1 and MHC antigens on human intrahepatic bile duct cells: effect of pro-inflammatory cytokines.
Human intrahepatic biliary epithelial cells were isolated from the livers of patients with primary biliary cirrhosis and from normal livers and established in primary culture. The in vitro expression of intercellular adhesion molecule-1, HLA class I, and HLA class II on biliary epithelial cells was studied in response to tumour necrosis factor-alpha (0-500 U/ml), interferon-gamma (0-500 U/ml), and interleukin-1 (0-5 U/ml) by immunohistochemical staining and a semiquantitative scoring system validated by spectrophotometry and previously validated by laser confocal microscopy. The non-stimulated expression of intercellular adhesion molecule-1 and HLA class II was higher on cells derived from the primary biliary cirrhosis liver than on cells from normal liver, a difference not seen with HLA class I expression. A statistically significant increase in intercellular adhesion molecule-1 expression was seen with all three cytokines in cells derived from both primary biliary cirrhosis and normal liver. Increase in HLA class I expression was seen only with interleukin-1 5 U/ml for cells derived from both normal and diseased liver. Increase in HLA class II expression was seen only with interferon-gamma 500 U/ml for cells derived from diseased liver and with interleukin-1 5 U/ml for cells derived from both diseased and normal liver. These data show that pro-inflammatory cytokines increase expression of intercellular adhesion molecule-1, HLA class I, and HLA class II on human intrahepatic biliary epithelial cells in vitro and are consistent with the hypothesis that these locally acting factors may play a part in the pathogenesis of immune mediated disorders such as primary biliary cirrhosis in which immune mediated bile duct damage occurs.
Bile Ducts, Intrahepatic↗
Medical complications of liver transplantation.
Liver transplantation poses enormous and complex medical problems. Of the infective complications, bacterial infections are the commonest overall, but the single commonest is cytomegalovirus and the most deadly are the fungal infections. Therapeutic options and possibilities for prophylaxis are improving. Rejection, both acute and chronic, is the other major cause of mortality, and the balance between immunosuppression and infection is difficult. Cyclosporin treatment contributes to renal impairment, hypertension, and multitudinous potential neurological problems. The risk of long-term neoplasia is unclear. Relatively more minor is the potential for osteoporosis and metabolic complications, such as diabetes and hyperlipidaemia. Hepatitis B disease has a sizable risk of recurrence, but the most recent prophylaxis regimes have improved relapse rates. Having survived the physical problems following transplantation, most of which occur in the first 6 months, there are considerable psychosocial adjustments to be made particularly in the case of children where growth and development may have been delayed. Despite all these difficulties, liver transplantation is an expanding and optimistic area with enormous potential.
Graft Rejection↗
Chronic rejection of the liver allograft.
Chronic rejection remains one of the major problems in the management of liver transplant recipients. Histologic diagnosis is central to the management of this condition. It remains difficult to predict cases that will progress toward irreversible rejection, because there are no early diagnostic features. Furthermore, the determination that irreversible rejection has occurred and retransplantation is required also is difficult. There remain many unanswered questions about the cause and pathogenesis of this process. The bile duct loss and arteriopathy parallel changes seen in chronic rejection of other organs. The extent to which this process is specific to the liver or is common to the other transplanted organs and mediated by an immune attack on the vascular bed is unknown. The precise position of HLA matching or mismatching as a risk factor for subsequent chronic rejection remains to be answered but in hepatic transplantation does not seem to be a major factor. The relation between the immunologic trigger of a graft and an aggressive arteriosclerosis is a major challenge, and a greater understanding of this process should provide some new therapeutic options in preventing the disease.
Adult↗
Detection of circulating intercellular adhesion molecule-1 in chronic liver diseases.
The leucocyte adhesion molecule intercellular adhesion molecule-1 is induced on bile ducts in patients with primary biliary cirrhosis and primary sclerosing cholangitis and may be involved in targeting immune damage to these structures. It has recently been reported that, when activated, in vitro lymphocytes release a soluble form of intercellular adhesion molecule-1 that can also be detected in human serum. Because it is functionally active, this circulating intercellular adhesion molecule-1 might play a role in regulating inflammation by blocking adhesion. We used an enzyme-linked immunosorbent assay to detect circulating intercellular adhesion molecule-1 in the serum of patients with primary biliary cirrhosis and primary sclerosing cholangitis. Levels of circulating intercellular adhesion molecule-1 were markedly elevated in primary biliary cirrhosis and primary sclerosing cholangitis when compared with other chronic liver diseases. Circulating intercellular adhesion molecule-1 is probably derived from activated lymphocytes rather than from bile ducts because biliary epithelial cells from patients with primary biliary cirrhosis did not release circulating intercellular adhesion molecule-1 when stimulated to express the membrane-bound molecule in vitro. These studies are the first to demonstrate circulating intercellular adhesion molecule-1 in chronic inflammatory diseases that are characterized by strong tissue expression of intercellular adhesion molecule-1 and as such suggest a potential immunoregulatory role for circulating adhesion molecules. The very high levels detected in primary biliary cirrhosis and primary sclerosing cholangitis probably reflect lymphocyte activation, which is further evidence of immune pathogeneses for these diseases.
Bilirubin↗
Long-term immunosuppression after liver transplantation: are steroids necessary?
Steroid therapy was withdrawn in 85% of 152 orthotopic liver transplant recipients with grafts surviving for more than 3 months, and 87% of these remained steroid-free. Steroid therapy was restarted in 8% for reasons other than rejection. The most common was conversion of immunosuppression because of cyclosporine nephrotoxicity. The incidence of rejection after steroid withdrawal was low: 3.8% for chronic rejection (CR) and 4.5% for acute rejection. Only 3 grafts (1.9%) were lost because of CR. No risk factors have been identified for the development of CR after steroid withdrawal, but a protective role for azathioprine has been suggested.
Adolescent↗
Treatment of acute rejection.
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Antibodies, Monoclonal↗
Endothelial cell damage in primary biliary cirrhosis: influence of cholestasis and immunological mechanisms.
In a study looking for evidence of endothelial cell damage in primary biliary cirrhosis, serum from patients was found to be significantly more cytotoxic to cultured endothelial cells in vitro than normal control serum (P less than 0.001). Serum also contained higher levels of von Willebrand factor antigen (vWFAg, a specific product of the endothelium) than control serum (P less than 0.001). Cytotoxicity correlated with serum levels of vWFAg (P less than 0.05) and with serum bilirubin (P less than 0.05). No correlations were found between cytotoxicity and circulating immune complexes, C-reactive protein or CH50. The study was controlled by serum from patients with other liver diseases. In these samples vWFAg (P less than 0.003), and bilirubin levels (P less than 0.001) were also raised relative to normal controls. vWFAg levels again correlated with levels of bilirubin (P less than 0.05). Tissue culture experiments showed that purified bilirubin was cytotoxic to human umbilical vein endothelial cells and induced the release of vWFAg. The case report of a patient with obstructive jaundice again indicated that levels of bilirubin and vWFAg were related. These results suggest that endothelial cell damage occurs in both primary biliary cirrhosis and to a lesser extent in other liver diseases, and may be mediated by cholestasis, not by humoral immunological mechanisms.
Bilirubin↗
Liver disease in a district hospital remote from a transplant centre: a study of admissions and deaths.
The profile of liver disease admissions and associated deaths in a district general hospital was studied to determine whether patients with end stage liver disease are appropriately referred for consideration of liver transplantation. Admission details were provided by the Office of Population Censuses and Surveys (OPCS) and their accuracy was assessed by case note analysis. According to OPCS, 77 patients with liver disease were admitted on 113 occasions between 1 January 1987 and 31 December 1989. The case notes of 74 (96%) were retrieved and examined. Only 64 (86%) had primary liver disease. Twenty four (31%) died of liver failure. Alcohol was the aetiological agent in two thirds. According to accepted criteria, 11 patients were suitable for liver transplant assessment but only three had been referred to a transplant centre. Of the remaining eight, five died during the study period. Two of the three patients referred died without transplantation; one underwent transplant and survived. There is discrepancy between OPCS data and true disease aetiologies, with approximately 40% under reporting of alcoholic liver disease. If this population is representative of the situation nationally, substantial numbers of patients with end stage liver disease might benefit from liver transplantation, but are not referred to a centre.
England↗
Human intrahepatic biliary epithelial cells proliferate in vitro in response to human hepatocyte growth factor.
In previous studies, intrahepatic human biliary epithelial cells (BEC) were isolated in high purity. However, these cells demonstrated only limited growth responses. Here we report that human BEC proliferate in response to human hepatocyte growth factor (hHGF), retain BEC-specific phenotype, and can be serially passaged. BEC showed dose-dependent growth in response to 0.01-100 ng/ml hHGF. The maximum S-phase labeling index reached 40% with half-maximal stimulation at 1 ng/ml. The response of cells from normal and primary biliary cirrhotic liver to hHGF was similar. Cultures were immunostained with specific antibodies and then processed for [3H]thymidine autoradiography. Proliferating cells expressed BEC-specific markers (HEA125 and CK-19), but were negative for desmin and factor VIII-related antigen. Occasional vimentin-positive cells were observed, but these were nonproliferative. In conclusion, cells responding to hHGF were clearly BEC in origin. The observation that HGF is mitogenic for BEC as well as hepatocytes has important implications. First, greater yields of intrahepatic BEC are available for subsequent studies of the pathogenesis and etiology of diseases of the biliary epithelium. Secondly, some means of regulating the cellular response to HGF in vivo must operate, in that HGF levels rise early after partial hepatectomy and yet BEC proliferate 24 h later than hepatocytes.
Animals↗
Cytomegalovirus surveillance following liver transplantation: does it allow presymptomatic diagnosis of cytomegalovirus disease?
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Adult↗
Orthotopic liver transplantation for hepatic GVHD following allogeneic BMT for chronic myeloid leukaemia.
A 21-year-old man who had an HLA-identical sibling donor BMT for chronic myeloid leukaemia developed grade IV acute GVHD of the liver that was unresponsive to corticosteroids and anti-IL2 receptor monoclonal antibody. He was treated with an orthotopic liver transplant and is currently well 6 months later with normal liver function and no evidence of GVHD in the transplanted liver.
Adult↗