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Biomedical subjects

J Neuberger

Publications and source records attributed to J Neuberger.

At least 73 records · Page 4Linked to original sources
PubMed1985

Antibody mediated hepatocyte injury in methyl dopa induced hepatotoxicity.

To investigate the mechanisms underlying the hepatotoxicity induced by methyl dopa, we have examined sera from nine patients with liver damage following the use of the drug for evidence of sensitisation to drug altered liver cell membrane antigens using both immunofluorescence and antibody dependent cell mediated cytotoxicity. Five sera induced significant cytotoxicity to hepatocytes isolated from rabbits pretreated with methyl dopa after exposure to the mixed function oxidase inducer, Arachlor 1254. Sera from 10 patients on methyl dopa but with normal liver function and 32 patients with other drug and viral induced liver damage, gave normal cytotoxicity values. Two of the antibody positive sera gave a specific immunofluorescence pattern at the periphery of human hepatocytes when tested on liver biopsy specimens taken from patients taking methyl dopa. These findings are consistent with the view that immune mechanisms directed against drug associated antigens are involved in severe liver damage from methyl dopa administration and that metabolic activation of the drug is implicated in the generation of drug associated antigen. The need for a combination of immune and metabolic factors may explain the rarity of this condition.

Aged↗
PubMed1985

Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis.

One hundred and eighty nine patients with primary biliary cirrhosis were entered into a double blind, placebo controlled randomised trial starting in January 1978 to assess the therapeutic value of d-penicillamine 1200 mg daily. Eighteen of the 98 patients receiving d-penicillamine and 22 of the 91 placebo treated patients died during the study. Thirty six per cent of those on d-penicillamine and 8% of those on placebo were withdrawn from the study. No difference in overall survival was noted between the two groups of patients whether the results were analysed for the entire period of observation or only during the period in which the patients were receiving therapy. The mortality rate of those receiving d-penicillamine in histological stage I to II, however, was one third of that of the placebo group although this difference did not reach statistical significance. Using the occurrence rate ratio as the statistical method of analysis, no effect of d-penicillamine was noted on any clinical, biochemical or histological features examined, except the serum alanine aminotransferase activity which was greater in those on active treatment. In this trial we have been unable to establish any therapeutic benefit from the drug.

Clinical Trials as Topic↗
PubMed1985

In vitro studies on the mechanism of increased serum IgM levels in primary biliary cirrhosis.

To evaluate the mechanisms underlying the increase in serum IgM in primary biliary cirrhosis (PBC) studies were designed to examine IgM production in vitro and to assess the relative contribution of intrinsic B cell activity and immunoregulatory T cell balance to IgM synthesis. The number of peripheral blood lymphocytes (PBL) producing IgM (spontaneous and pokeweed mitogen (PWM) stimulated) at the end of a seven day culture period was similar in PBC patients and control subjects while the amount of IgM synthesized (spontaneous and PWM stimulated) during this period was significantly greater in the patient group, implying that the amount of IgM produced per B cell was increased in PBC. Co-culture of autologous and allogeneic T and B lymphocytes and irradiation of T lymphocytes from patients and normal subjects clearly implicated abnormal suppressor T cell function, rather than autonomous B cell hyperactivity, as the cause of the increased IgM synthesis. Direct studies of T cell function indicated that although concanavalin A (Con A) activated suppressor cells inhibited proliferation of IgM producing B cells in the majority of PBC patients, they were unable to inhibit IgM synthesis. The demonstration of a disparity between IgM synthesis and the proliferation of IgM-producing B cells, together with the observation that the abnormality of T cell function is largely confined to the control of IgM secretion, is consistent with the presence of at least two different suppressor subpopulations regulating IgM production. In PBC the main suppressor cell abnormality seems to affect regulation of IgM secretion rather than B cell proliferation.

B-Lymphocytes↗
PubMed1985

Long-term use of cyclosporin in liver grafting.

The clinical course of 29 liver graft recipients in the Cambridge/King's College Hospital series who have received cyclosporin A (CyA) for up to five years (median 40 months) was analysed with particular reference to the immunosuppressive effectiveness and adverse effects of the drug. Eight patients had been maintained on prednisolone and azathioprine for two to six years before treatment was changed to cyclosporin A and the remainder were started on cyclosporin A after operation. Results in both groups over a one to five year study period are similar, and showed that cyclosporin A was effective in maintaining adequate immunosuppression, allowing complete withdrawal of prednisolone in 16 patients. Episodes of rejection were observed in only three patients and in two of these it was of the chronic 'vanishing bile duct' variety. Some evidence of nephrotoxicity (serum creatinine greater than 150 mumol/l) occurred in 72 per cent (21 of 29 patients) but it was necessary to discontinue treatment in only two. Hypertension, occasionally of sudden onset, was found in nine patients and led to the withdrawal of the drug in two. Additional hypotensive drug treatment was required in five. In one other patient cyclosporin A was discontinued on account of severe headaches. Cyclosporin A was withdrawn in two further patients. Withdrawal led to considerable risk of acute rejection and increased doses of corticosteroids as well as substitution of azathioprine were required at that time.

Adolescent↗
PubMed1985

[Centrolobular liver cell necroses following occupational halothane contact. Association with antibodies to halothane altered liver cell components].

A report is given on a 24 year old nurse, who developed two episodes of fever, chills and malaise with high serum enzyme levels and histologic proof of extensive centrolobular hepatic necrosis in association with vocational halothane exposure in the operating theatre. A cause-effect relationship was suggested by the demonstration of antibodies against halothane-altered hepatocyte membrane components. Also, there was no indication of other known causes of a cytotoxic liver reaction. In certain predisposed individuals, halothane even in subanaesthetic concentrations is apparently able to induce liver cell damage. Only six further reports on such liver injuries in medical personnel could be found in the literature.

Adult↗
PubMed1984

An enzyme-linked immunosorbent assay for detection of antibodies against halothane-altered hepatocyte antigens.

Patients with massive liver cell necrosis that may follow halothane anaesthesia have a high incidence of circulating antibodies against halothane-induced hepatocyte antigens. In order to provide an objective and quantitative method for the detection of these antibodies, an enzyme-linked immunosorbent assay has been developed. Sera, after absorption with normal rabbit liver microsomal fraction, are tested for binding to microsomal fractions from control and halothane-pretreated rabbits. Those containing antibodies against halothane-induced determinants give significantly enhanced binding to halothane-altered fractions; this specificity was verified by absorption experiments. Using this method, halothane-related antibodies were detected in sera from 16/24 patients with halothane-associated liver failure, at titres ranging from 1:100 to 1:25600. Such antibodies were not detectable in sera from 26 normal blood donors, 5 healthy anaesthetists, 12 patients who had received multiple halothane anaesthetics but had normal liver function tests and 32 patients with a variety of other liver diseases. This rapid and reproducible assay should be of value for the detection of antibodies and for detailed investigation of patient antibody responses, and also for characterization of the route of production and metabolism of the antigen.

Absorption↗
PubMed1984

A simple enzyme-linked immunosorbent assay for detection of anti-mitochondrial antibodies.

An enzyme-linked immunosorbent assay (ELISA) has been developed for detection of anti-mitochondrial antibodies (AMA) in patients' sera. Results are expressed as a mitochondrial binding index, calculated from binding of patients' antibodies to rabbit liver mitochondrial fraction and total liver homogenate. The incidence of AMA detectable by this method in 22 sera from patients with primary biliary cirrhosis was identical with that obtained by conventional immunofluorescence testing (86%), and there was a highly significant correlation between titres determined by the two methods (r = 0.828; P less than 0.01) although ELISA titres were far higher. AMA were also detectable by ELISA in sera from 9/22 patients with chronic active hepatitis, 1/38 patients with other liver diseases, 3/16 patients with syphilis, 2/16 patients with non-hepatic autoimmune diseases and 0/29 normal blood donors; of these, only 2 chronic active hepatitis sera were positive for AMA by immunofluorescence. The ELISA titre was significantly correlated with the mitochondrial binding index determined at a serum dilution of 1:200 (r = 0.793; P less than 0.01), allowing an estimate of antibody titre to be made from ELISA screening at this single serum dilution. This assay, which is simple and reproducible, may be of value as an objective method of screening for AMA.

Autoantibodies↗
PubMed1984

Recurrence of autoimmune chronic active hepatitis following orthotopic liver grafting.

In a 26-year-old woman who had received an orthotopic liver graft for end-stage autoimmune chronic active hepatitis, signs indicative of the original disease became apparent 18 months after transplantation, at a time when the maintenance dose of prednisolone had been reduced to 3 mg daily. In addition to anorexia, nausea, and weight loss there was a reappearance of spider naevi, serum autoantibodies, and elevated levels of immunoglobulin G. Features typical of chronic active hepatitis were observed on examination of the liver biopsy, and both the clinical and histological pictures were unlike those of other possible causes of liver dysfunction, such as chronic rejection, cyclosporine hepatotoxicity, and non-A non-B chronic hepatitis. Following substitution of azathioprine for cyclosporine and an increased dose of prednisolone (20 mg daily), there was a rapid improvement in the clinical state and both serum transaminases and immunoglobulins returned to normal values. Histological appearances in a repeat biopsy taken six months later were consistent with chronic active hepatitis in remission. This case provides further evidence of the importance of host factors in the pathogenesis of chronic active hepatitis and emphasizes the necessity for selecting appropriate immunosuppressive therapy in such patients after transplantation.

Adult↗
PubMed1984

Pharmacokinetic study of cyclosporin A (Sandimmun) in patients with primary biliary cirrhosis.

The pharmacokinetics of cyclosporin A (CS-A) were studied in 10 patients with primary biliary cirrhosis (PBC) after oral administration in steady state. Mean values for area under the blood concentration-time curve (AUC), time to maximal blood concentration (tmax), maximal blood concentration (Cmax) and elimination half-life (t1/2,z) were similar to results of previous studies in transplant patients. The variation between patients was large. No significant correlations of pharmacokinetic data with biochemical or histological parameters were found. Because of the high variability of pharmacokinetic parameters, patients with PBC treated with CS-A need to be regularly controlled for nephrotoxicity by estimation of serum creatinine and bioavailability (trough blood levels).

Adult↗
PubMed1984

Antibodies to alcohol altered liver cell determinants in patients with alcoholic liver disease.

Circulating antibodies reacting specifically with hepatocytes isolated from ethanol pretreated rabbits have been demonstrated by two techniques - induced cytotoxicity and immunofluorescence. In the cytotoxicity assay antibodies were found in seven of 19 (39%) of patients with alcoholic fatty liver (with or without fibrosis), six of 13 (46%) of those with alcoholic hepatitis, 15 of 36 (43%) of those with cirrhosis, and seven of 14 patients (50%) of those with hepatitis and cirrhosis. In the immunofluorescence studies, nine of 15 sera induced a granular pattern of fluorescence on the ethanol pretreated hepatocytes; two sera which induced significant cytotoxicity did not induce immunofluorescence. No ethanol related antibodies were found in normal individuals or in patients with other types of acute or chronic liver disease. These results show that antibodies directed against ethanol altered liver cell determinants are present in the serum of 43% of patients with alcoholic liver disease, and suggest a mechanism whereby chronic alcohol consumption may, by inducing antigenic changes in hepatocyte membranes, trigger a cell damaging immune reaction.

Adult↗
PubMed1984

Hepatocellular carcinoma in primary biliary cirrhosis: detection by alpha-fetoprotein estimation.

Serial estimations of serum alpha-fetoprotein in 130 white patients from the United Kingdom with primary biliary cirrhosis who were followed for periods of 1-52 mo revealed 5 cases of hepatocellular carcinoma; all were subsequently confirmed histologically. At the time alpha-fetoprotein was first noted to be elevated, none had signs or symptoms of tumor development. Of the 52 patients who died during the follow-up period, hepatocellular carcinoma was the cause of death in 3 (33%) of the 9 men, and 2 (5%) of the 43 women. Allowing for the marked predominance of women among patients with primary biliary cirrhosis, hepatocellular carcinoma may be no less frequent in primary biliary cirrhosis than in other types of cirrhosis.

Adult↗
PubMed1983

Specific serological markers in the diagnosis of fulminant hepatic failure associated with halothane anaesthesia.

The aetiology of massive liver-cell necrosis which developed in 16 patients following halothane anaesthesia was investigated by means of new serological techniques. In eight patients a specific halothane-related antibody was found, indicating that these patients were sensitized to halothane-altered liver-cell membrane components. In four patients, hepatitis A viral infection was responsible and among the remainder one was receiving anti-tuberculous drugs and one had received a blood transfusion, thus raising the possibility of a non-A non-B viral infection. There were no biochemical or histological differences between patients in the three groups.

Acute Disease↗
PubMed1983

Effect of polyunsaturated phosphatidylcholine on immune mediated hepatocyte damage.

Studies were carried out to investigate the mechanisms underlying the reduction of hepatocellular necrosis observed when polyunsaturated phosphatidylcholine was administered to patients with HBsAg negative chronic active hepatitis. After oral administration of the agent, the susceptibility of rabbit hepatocytes to both antibody dependent cell mediated cytotoxicity and mitogen induced lymphocyte cytotoxicity was substantially reduced. Short term in vitro incubation of either the hepatocytes or lymphocytes with polyunsaturated phosphatidylcholine had no effect on antibody dependent cell mediated cytotoxicity. As it has been shown that orally administered polyunsaturated phosphatidylcholine can be incorporated into the liver cell membrane, it is possible that polyunsaturated phosphatidylcholine exerts its effect by blocking the interaction between immune effector cells and hepatocytes.

Adult↗
PubMed1982

Recurrence of primary biliary cirrhosis after liver transplantation.

Three patients who had undergone orthrotopic liver transplantation for primary biliary cirrhosis and were being maintained on immunosuppressive therapy were investigated 31/2 to 41/2 years later because of the redevelopment of pruritus and mild jaundice. In one patient pigmentation was again evident, and all three had a rise in the titer of serum mitochondrial antibody after an initial fall. Liver histology showed features of primary biliary cirrhosis with non-suppurative destructive cholangitis, lymphoid aggregates, and increased deposition of copper-binding protein in the absence of cholestasis. None of these features was found in patients who had received grafts for other conditions and had lived for comparable periods, nor were they found in patients who had had rejection with bile-duct abnormalities. The overall findings indicate a recurrence of primary biliary cirrhosis in the donor organ.

Adult↗
PubMed1981

Improved survival after orthotopic liver grafting.

A total of 108 orthotopic liver transplants have been carried out in the Cambridge/King's College Hospital series. Over 13 years, changes in patient selection, immunosuppression, and surgical and anaesthetic techniques have led to a steady improvement in results. Results obtained in the last 22 patients indicated that over half survive for one year. Although at considerable risk during the operation, patients with non-malignant cirrhotic diseases who survive one year have a good long-term chance of survival

Adolescent↗