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E R Dickson

Publications and source records attributed to E R Dickson.

At least 91 records · Page 5Linked to original sources
PubMed1992

Comparative immunoreactive profiles of Japanese and American patients with primary biliary cirrhosis against mitochondrial autoantigens.

Primary biliary cirrhosis (PBC) has been described among various ethnic and racial populations in all parts of the world. However, the incidence and prevalence of PBC varies considerably in different geographic areas. It has the highest frequency in Northern Europe, is considerably lower in Japan and still lower in other parts of Asia. There has not hitherto been a detailed immunological profile of antimitochondrial antibodies according to geographic region. We have used recombinant or purified preparations from the 2-oxo-acid dehydrogenase enzyme complexes, the major mitochondrial autoantigens in PBC (PDC-E2, BCOADC-E2, OGDC, protein X and PDC-E1 alpha) to compare the reactivity of sera from either similarly staged sera from Japanese (n = 23) or American-Caucasian patients (n = 39) with PBC. In all cases, the first available sera following diagnosis was selected. Interestingly, only 65% of Japanese patients reacted by ELISA with PDC-E2 compared with more than 95% of the North American group. Moreover, the level of enzyme-inhibitory antibodies to PDC was lower in the Japanese. Our findings prompt the need for characterization of specific susceptibility genes and environmental factors in various parts of the world to clarify the etiology of PBC.

Antigen-Antibody Reactions↗
PubMed1992

A prospective study of pulmonary function and gas exchange following liver transplantation.

Pulmonary function and gas exchange were prospectively studied in 95 patients before and 9 to 15 months following liver transplantation. Pretransplant, the most common PF abnormality was impaired efficiency of gas exchange as measured by Dss. As a group, the mean Dss was 78.0 +/- 16.6 percent predicted and was found to be less than 80 percent predicted in 50 patients. As a group, patients with the most severe liver diseases clinically (Child's C classification) had the lowest mean Dss pretransplant. Posttransplant, three findings were of clinical importance: PaCO2 significantly improved posttransplantation, suggesting a resolution of pretransplant respiratory alkalosis. Expiratory airflow obstruction, measured by a change in the FEV1/FVC, was extremely uncommon posttransplant. Mean Dss improved significantly in patients with Child's C severity of liver disease. The most frequent deteriorations in Dss statistically were associated with posttransplant thoracotomy, ARDS, nonspecific pneumonitis, significant pleural effusions and hepatic retransplantation.

Female↗
PubMed1992

M4 and M9 antibodies in the overlap syndrome of primary biliary cirrhosis and chronic active hepatitis: epitopes or epiphenomena?

Before the identification of the major mitochondrial antigens of primary biliary cirrhosis as components of the 2-oxo-acid dehydrogenase enzyme family, mitochondrial autoantigens were believed to be extremely heterogeneous and were divided into nine subtypes termed M1 to M9. This classification was based on the data derived from the relatively nonspecific biochemical and immunological techniques that were available. After the cloning and definition of the major autoantigens, more than 95% of the sera of patients with primary biliary cirrhosis were found to react with components of the 2-oxo-dehydrogenase enzymes; these enzymes correspond to the old M2 classification. Two other "M" species, dubbed M4 and M9, have attracted significant attention because they have been postulated to be prognostic indicators and more recently have been tentatively identified respectively as sulfite oxidase (EC 1.8.3.1) and glycogen phosphorylase (EC 2.4.1.1). Indeed, patients with the "overlap syndrome" are reported to have antibodies to M4 and a poor prognosis, whereas patients with antibodies to M9 have a favorable prognosis. To address the significance and definition of M4 and M9, we performed in-depth studies of sera from 11 patients with the overlap syndrome, 75 patients with primary biliary cirrhosis, 19 chronic active hepatitis patients, 13 patients with primary sclerosing cholangitis, 10 patients with cholangiocarcinoma, 20 patients with systemic lupus erythematosus, 20 patients with alcoholic cirrhosis, 17 patients with scleroderma and 30 normal individuals, using techniques of ELISA, complement fixation, immunoblotting and enzyme inhibition. We report herein that we were unable to show any disease-specific reactivity toward the proposed M4 and M9 antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma, Bile Duct↗
PubMed1992

Selection and timing of liver transplantation in primary biliary cirrhosis and primary sclerosing cholangitis.

In summary, we answer the three questions we have previously posed: (a) Can liver transplantation prolong survival? Evolving data from several centers indicate that liver transplantation indeed prolongs survival in patients with PBC and PSC as compared with estimated survival using disease-specific risk scores based on the natural history of PBC and PSC. (b) Can we optimize timing of liver transplantation? Although many factors enter into the timing of liver transplantation, including when the patient is actually referred for liver transplantation and the individual desires of the patient to pursue liver transplantation, evidence is growing that having patients with chronic liver diseases like PBC and PSC undergo transplantation a little earlier in the course of the disease rather than waiting until the patients have experienced life-threatening complications or are on life-support measures can indeed improve early postliver transplant survival. In patients with PBC and PSC, the survival risk score, which reflects disease severity, can serve as an objective measurement to assess and evaluate the effect of liver disease severity on transplant outcome. Indeed, a number of studies have strongly suggested that optimal timing of liver transplantation may indeed be important to improve outcome, decrease morbidity and decrease cost. (c) Does the present allocation system in the United States allow for optimal use of our scarce donor organ resource?(ABSTRACT TRUNCATED AT 250 WORDS)

Cholangitis, Sclerosing↗
PubMed1991

The metabolic bone disease of primary sclerosing cholangitis.

The incidence and severity of osteopenic bone disease in primary sclerosing cholangitis is poorly defined. Clinical, biochemical and radiographic assessment and bone mineral density measurements of the lumbar spine were carried out in two groups of patients. Group 1 consisted of 30 patients with advanced primary sclerosing cholangitis; group 2 consisted of 18 patients with newly diagnosed primary sclerosing cholangitis. Only one patient had bone pain. All patients were normocalcemic; two had elevated serum parathormone levels. Fourteen patients (47%) from group 1 but no patients from group 2 had low serum 25-hydroxyvitamin D levels. Mean bone mineral density was significantly reduced in group 1 patients (0.97 +/- 0.04 gm/cm2) compared with age-matched and sex-matched controls (1.25 +/- 0.01 gm/cm2, p less than 0.0001), and in 15 patients (50%) bone mineral density was below the fracture threshold (0.98 gm/cm2). The bone mineral density in group 2 was not significantly different from controls, and no patient was below the fracture threshold. In neither group did bone mineral density correlate with serum bilirubin, 25-hydroxyvitamin D, fecal fat excretion, previous drug therapy or the presence of chronic ulcerative colitis. Histomorphometrical examination of bone from four group 1 patients showed increased bone resorption, reduced bone formation, moderate-to-severe osteopenia and no osteomalacia. In conclusion, severe osteopenic bone disease is common in advanced primary sclerosing cholangitis and, like that seen in other cholestatis diseases, is consistent with osteoporosis.

Adult↗
PubMed1991

Rates of vertebral bone loss before and after liver transplantation in women with primary biliary cirrhosis.

Atraumatic fractures caused by osteoporosis may be a serious complication of primary biliary cirrhosis. Mean (+/- S.D.) bone mineral density in the lumbar spine in 210 ambulatory women with primary biliary cirrhosis was 1.02 +/- 0.19 gm/cm2, 7% lower than that in 139 age-matched normal women (after adjustment for age and body weight) (p less than 0.001). Bone mineral density in the lumbar spine was inversely related to a risk score index of liver disease severity (r = -0.29, p less than 0.001). The mean rate of bone loss in 105 of these 210 women was 2%/yr +/- 4%/yr, twice as great as in the 139 normal women (p less than 0.02). In 20 women with primary biliary cirrhosis followed up after orthotopic liver transplantation, bone mineral density in the lumbar spine decreased at 3 mo (p less than 0.01), and this decrease may have resulted in atraumatic fractures in 13 of them. Bone mineral density in the lumbar spine then increased (p less than 0.01) so that by 12 mo the median bone mineral density in the lumbar spine was similar to that before transplantation and by 24 mo it was 5% above it. Therefore we conclude that the progressive bone loss observed in primary biliary cirrhosis (which is further accentuated immediately after transplantation) may be halted, and the bone mass may be restored toward normal within 2 to 3 yr after orthotopic liver transplantation.

Absorptiometry, Photon↗
PubMed1991

Primary biliary cirrhosis: relation between hepatic function and pulmonary function in patients who never smoked.

We studied the relationship between selected variables of hepatic and pulmonary function in 47 patients with primary biliary cirrhosis, who were participating in a prospective study to assess sequential pulmonary function at yearly intervals. An additional 20 patients with primary biliary cirrhosis, who were liver transplant candidates awaiting transplantation, were studied. None of the 67 patients ever smoked cigarettes. Severity of primary biliary cirrhosis was characterized by histological stage and the Mayo risk score derived from a Cox regression model that used the following variables: serum bilirubin and serum albumin levels, age, prothrombin time and clinical severity of edema. Pulmonary function assessment included key variables describing expiratory airflow (forced expiratory volume in 1 sec divided by forced vital capacity) and efficiency of gas exchange (steady-state diffusing capacity for carbon monoxide). We found a significant relationship between histological stage of primary biliary cirrhosis and steady-state diffusing capacity (p = 0.02) and between the Mayo risk score for disease severity and steady-state diffusing capacity (p = 0.03). Progressive deterioration of steady-state diffusing capacity was associated with increasing severity of primary biliary cirrhosis. No relationship existed between pulmonary function and the presence of sicca complex or Sjögren's syndrome or the clinical manifestations of portal hypertension (e.g., esophageal varices, ascites and splenomegaly). No significant relationship existed between expiratory airflow and severity of primary biliary cirrhosis. We conclude that in patients with primary biliary cirrhosis who have never smoked, a statistically significant relationship exists between the severity of the liver disease and the efficiency of gas exchange measured by steady-state diffusing capacity.(ABSTRACT TRUNCATED AT 250 WORDS)

Humans↗
PubMed1990

A controlled trial of cyclosporine in the treatment of primary biliary cirrhosis.

Primary biliary cirrhosis is a progressive disease of the liver characterized by the immunologic destruction of bile ducts; effective therapy is lacking. We therefore evaluated the safety and efficacy of low-dose cyclosporine in 29 patients with primary biliary cirrhosis without evidence of damage to the lobular architecture (precirrhotic disease) or portal hypertension. The patients were randomly assigned to receive either cyclosporine (4 mg per kilogram of body weight per day) or placebo. After one year 17 of the 19 patients assigned to cyclosporine had improvement or stability in their degree of fatigue, and 18 in their degree of pruritus. In contrast, among the 10 patients assigned to placebo, fatigue increased in 4 (P less than 0.06) and pruritus worsened in 6 (P less than 0.001). Those assigned to cyclosporine also had significant decreases in serum levels of bilirubin, alanine aminotransferase, alkaline phosphatase, gamma globulin, and the titer of antimitochondrial antibodies. For the 20 patients who have completed two years in the study, liver biopsies (coded specimens) showed evidence of histologic progression in only 1 of 13 patients in the cyclosporine group, as compared with 5 of 7 in the placebo group (P less than 0.003). No patient has permanently discontinued cyclosporine because of side effects; however, signs of nephrotoxicity developed in 12 of 19, and 9 of 19 had increased blood pressure. We conclude that in patients with precirrhotic primary biliary cirrhosis, immunosuppressive therapy with cyclosporine is promising and deserves further evaluation.

Alanine Transaminase↗
PubMed1990

The relative affinity of recombinant dihydrolipoamide transacetylase for autoantibodies in primary biliary cirrhosis.

In normal individuals there is an adaptive immune response to a foreign antigen in which antibodies of increasing affinity are produced with time. This is not always true of an autoimmune response. However, because only a limited number of autoantigens have been cloned or purified, this issue has not been studied well. In primary biliary cirrhosis the predominant manifestation of autoimmunity is antimitochondrial antibodies that react with dihydrolipoamide transacetylase. The availability of recombinant dihydrolipoamide transacetylase and the development of a rapid and reproducible enzyme-linked immunosorbent assay for autoantibodies has allowed us to address the affinity of autoantibodies using thiocyanate inhibition. Thiocyanate is a chaotropic compound known to inhibit antigen-antibody binding in a concentration-dependent manner. We used this property to inhibit the binding by enzyme-linked immunosorbent assay of human recombinant dihydrolipoamide transacetylase with serum autoantibodies from 55 patients with primary biliary cirrhosis. The relative affinity and serum autoantibody titers were then compared with the histological stage of the liver biopsy sample. Interestingly, we found a considerable heterogeneity of relative affinities. These relative affinities did not correlate with the histological stage or the serum titer of antimitochondrial antibodies. However, the ability of serum autoantibodies to inhibit intact primary biliary cirrhosis enzyme activity was found to correlate highly (R2 = 0.751) with the relative affinity. Thus there are profound differences between patients with respect to qualitative expression of autoantibodies. The significance of this data will be unclear until more is determined regarding the nature of the epitope that drives T cells and leads to B-cell responses.

Acetyltransferases↗
PubMed1990

Inhibition of alpha-ketoglutarate dehydrogenase activity by a distinct population of autoantibodies recognizing dihydrolipoamide succinyltransferase in primary biliary cirrhosis.

Sera from patients with primary biliary cirrhosis contain autoantibodies that recognize mitochondrial proteins. Five of the target autoantigens have now been identified as enzymes of three related multienzyme complexes: the pyruvate dehydrogenase complex, the branched chain alpha-ketoacid dehydrogenase complex and the alpha-ketoglutarate dehydrogenase complex. Each complex consists of component enzymes designated E1, E2 and E3. In this report, we confirm that primary biliary cirrhosis sera react with dihydrolipoamide succinyltransferase, the E2 component of alpha-ketoglutarate dehydrogenase complex. Seventy-three of 188 (39%) primary biliary cirrhosis sera reacted with alpha-ketoglutarate dehydrogenase complex-E2 when immunoblotted against purified alpha-ketoglutarate dehydrogenase complex; one of these sera also reacted with the E1 component. In addition, primary biliary cirrhosis sera possessing alpha-ketoglutarate dehydrogenase complex-E2 reactivity specifically inhibited enzyme function of alpha-ketoglutarate dehydrogenase complex. Enzyme activity was not affected by primary biliary cirrhosis sera that contained autoantibodies to pyruvate dehydrogenase complex-E2 and/or branched chain alpha-ketoacid dehydrogenase complex-E2, which lacked alpha-ketoglutarate dehydrogenase complex-E2 reactivity. Furthermore, affinity-purified primary biliary cirrhosis sera against alpha-ketoglutarate dehydrogenase complex-E2 inhibited only alpha-ketoglutarate dehydrogenase complex activity but did not alter enzyme activity of either pyruvate dehydrogenase complex or branched chain alpha-ketoacid dehydrogenase complex. Finally, alpha-ketoglutarate dehydrogenase complex-E2 specific affinity-purified antisera did not react on immunoblot with any component enzymes of pyruvate dehydrogenase complex or branched chain alpha-ketoacid dehydrogenase complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1990

Diminished survival in asymptomatic primary biliary cirrhosis. A prospective study.

Data from 73 asymptomatic patients with primary biliary cirrhosis were analyzed to determine clinical course and long-term survival. Of these, 44 entered a D-penicillamine treatment trial; 29 qualified but chose not to participate. Median follow-up was 7.6 yr (range, 2.8-12.2 yr). Liver biopsy at the initial visit showed advanced disease (fibrosis, cirrhosis) in 61% of the patients. During prospective clinical follow-up, which was available for 37 of the 44 study patients, one or more symptoms of liver disease developed in 33 (89%); esophageal varices were found in 15 (41%), and histologic progression to cirrhosis was found in 20 (67%) of the 30 precirrhotic patients. Significant (p less than 0.01) biochemical progression was reflected by a decrease in mean serum albumin concentrations and an increase in mean serum bilirubin levels in 32 patients followed for 4-6 yr. Survival data were available for all 73 patients; 17 died (11 secondary to liver failure), and 1 underwent liver transplantation. These patients had a 4-fold increase in mortality rate (p less than 0.001) compared with the U.S. population matched for age, race, and sex.

Adult↗
PubMed1990

Intrapulmonary vascular dilatations (IPVD) in liver transplant candidates. Screening by two-dimensional contrast-enhanced echocardiography.

Intrapulmonary vascular dilatations (IPVD) are extrahepatic complications of acute and chronic liver disorders that can result in severe hypoxemia. Contrast-enhanced (CE) echocardiography provides a noninvasive method to detect right-to-left shunting associated with IPVD. We prospectively studied 40 consecutive liver transplant candidates to determine the relationship between CE echocardiography, arterial blood gases, and standard pulmonary function tests. Two patients had technically unacceptable results of echocardiographic studies. Thirty-eight patients had acceptable results of studies; seven (18.4 percent) of 38 were hypoxemic (PaO2 less than 70 mm Hg). Thirty-one patients (81.6 percent) had PaO2 greater than or equal to 70 mm Hg. Positive CE echocardiograms suggesting IPVD were found in five (13.2 percent) of 38. Three (9.7 percent) of the 31 patients with PaO2 greater than or equal to 70 mm Hg had positive CE echocardiograms. Two (28.6 percent) of the seven hypoxemic patients had positive CE echocardiography. Mean PaO2 and pulmonary function parameters were not significantly different between those with positive CE echocardiogram compared with those with normal CE echocardiograms. We conclude that for our group of liver transplant candidates, (1) IPVD as suggested by CE echocardiography were not uncommon (13.2 percent), and (2) positive CE echocardiography could be documented in patients who were not hypoxemic (9.7 percent).

Adult↗
PubMed1989

Efficacy of liver transplantation in patients with primary biliary cirrhosis.

No controlled trials have been performed to assess the efficacy of liver transplantation. Because of the marked improvement in survival after liver transplantation since 1981, random assignment of patients to a control group not undergoing transplantation is considered clinically inappropriate. To assess the efficacy of liver transplantation in patients with primary biliary cirrhosis, we compared survival in 161 patients with this diagnosis who had undergone a liver transplantation with survival in patients with the same diagnosis who had been treated conservatively. The comparison was performed with use of a recently developed statistical technique, the Mayo model. All patients had undergone liver transplantation between March 1980 and June 1987 and were followed for a median of 25 months. Three months after liver transplantation, the Kaplan-Meier survival probabilities in the recipients were substantially higher than the Mayo-model "simulated-control" survival probabilities (P less than 0.001). At two years, the Kaplan-Meier survival probability was 0.74, whereas the mean Mayo-model survival probability was 0.31. The patients who were at low risk according to the Mayo model had the best probability of survival after liver transplantation; however, patients at all risk levels who had undergone liver transplantation had higher probabilities of survival that those who had not. We conclude that liver transplantation is an efficacious treatment in patients with advanced primary biliary cirrhosis.

Follow-Up Studies↗
PubMed1989

Antimitochondrial antibodies of primary biliary cirrhosis recognize dihydrolipoamide acyltransferase and inhibit enzyme function of the branched chain alpha-ketoacid dehydrogenase complex.

Antimitochondrial antibodies (AMA) recognizing the acetyltransferase (E2) of the pyruvate dehydrogenase (PDH) complex have been previously well-documented and the immunodominant epitope mapped. In this study, we demonstrate that sera from patients with primary biliary cirrhosis (PBC) react with another lipoic acid containing acyltransferase enzyme, namely the E2 of the branched chain alpha-ketoacid dehydrogenase (BCKD) complex. Indeed, 85/120 (71%) sera from patients with PBC reacted with BCKD-E2 by immunoblotting against purified BCKD complex. In contrast, sera from patients with chronic active hepatitis or progressive sclerosing cholangitis as well as sera from healthy volunteers did not react with any component enzymes of the BCKD complex. More importantly, BCKD enzyme activity was inhibited after incubation of the BCKD complex with either PBC sera against BCKD-E2 or with affinity purified antisera to BCKD-E2. Enzyme activity was unaltered by control sera or with PBC sera that reacted with PDH-E2 but not BCKD-E2. Furthermore, immunoblots of purified mitochondria probed with PBC sera absorbed with BCKD-E2 demonstrated that BCKD-E2 and PDH-E2 are each recognized by distinct AMA populations which do not cross-react. In addition, affinity purified PBC sera against BCKD-E2 did not react with PDH-E2 nor inhibit PDH enzyme activity, thus providing further evidence that BCKD-E2 and PDH-E2 are recognized by separate AMA. These data further suggest that the BCKD-E2 epitope recognized by AMA contains, or is close to, a functional domain of this enzyme. The availability of cDNA clones encoding BCKD-E2 and PDH-E2 will allow the study of how key metabolic enzymes may be involved in the immunology and pathology of PBC.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1989

Reactivity of primary biliary cirrhosis sera with a human fetal liver cDNA clone of branched-chain alpha-keto acid dehydrogenase dihydrolipoamide acyltransferase, the 52 kD mitochondrial autoantigen.

Antimitochondrial autoantibodies recognizing 68 to 74 and 50 to 52 kD inner membrane mitochondrial antigens are characteristically present in sera of patients with primary biliary cirrhosis. The biochemical identification of the antigens, however, has remained elusive. We report herein that the 52 kD antigen is the dihydrolipoamide acyltransferase of the branched-chain alpha-keto acid dehydrogenase complex. This was demonstrated by three experiments through the use of recombinant fusion protein expressed in Escherichia coli from a cDNA insert encoding the human autoantigen. First, 33 of 37 primary biliary cirrhosis patients exhibiting reactivity toward the 50 to 52 kD mitochondrial antigen by immunoblotting also showed reactivity toward the recombinant fusion protein. Second, absorption of primary biliary cirrhosis sera with recombinant fusion protein, but not with an irrelevant recombinant clone, the F-specific rat liver antigen, was effective in absorbing out reactivity against the 50 to 52 kD mitochondrial antigen but not the 68 to 74 kD antigen. Third, complete removal of reactivity toward all four different isoelectric point polypeptides at 50 to 52 kD was observed in two-dimensional gel analysis. Furthermore, primary biliary cirrhosis sera were analyzed with mitochondria from three sources, rat liver, human placenta and bovine heart, in order to compare reactivity patterns and to determine precisely the comparative molecular weights of the autoantigens in the three species. The availability of recombinant autoantigens will provide improved diagnostic tests and, more importantly, will allow definite issues in primary biliary cirrhosis to be studied, including identification of immunodominant epitopes, the significance of autoantigen recognition and the establishment of autoreactive T cell clones.

Acyltransferases↗