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Biomedical subjects

M F Sorrell

Publications and source records attributed to M F Sorrell.

At least 37 records · Page 2Linked to original sources
PubMed1997

The role of the transjugular intrahepatic portal-systemic shunt in the management of variceal bleeding.

For patients who present with variceal bleeding refractory to endoscopic and pharmacologic methods, TIPS is a new and effective therapy. Stents are used in selected patients with decompensated liver disease and those who anticipate liver transplantation within 6 to 12 months. Surveillance of TIPS with ultrasound, with or without venography, is recommended to diagnose and treat stenosis or occlusion before variceal hemorrhage recurs. Hepatic encephalopathy may develop in a subset of patients, but it is usually well controlled with conservative measures. Child-Pugh and APACHE scores are predictive of patient survival after TIPS. Randomized controlled trials will be necessary to assess whether TIPS is useful, safe, and cost effective for the management of variceal bleeding in patients with end stage liver disease.

Esophageal and Gastric Varices↗
PubMed1997

Epitope characterization of malondialdehyde-acetaldehyde adducts using an enzyme-linked immunosorbent assay.

Malondialdehyde (MDA) and acetaldehyde react together with proteins in a synergistic manner and form hybrid protein adducts, designated as MAA adducts. In a previous study, a polyclonal antibody specific for MAA-protein adducts was used in an immunoassay to detect the presence of MAA adducts in livers of ethanol-fed rats. In the present study, the specific epitope recognized by the antibody was defined and the chemistry of MAA adduct formation was further characterized. When several synthetic analogs were tested for their ability to inhibit antibody binding in a competitive ELISA, the results indicated that the major determinant of antibody binding was a highly fluorescent cyclic adduct composed of two molecules of MDA and one of acetaldehyde. The structure of this adduct was shown to be a 4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde derivative of an amino group of a protein. Examination of MAA adduct formation with a variety of proteins indicated that in addition to this specific fluorescent adduct, MAA adducts were also comprised of other nonfluorescent products. The amount of fluorescent epitopes present on a given protein was the major determinant of antibody binding as assessed in a competitive ELISA, although the efficiency of inhibition of antibody binding by these fluorescent epitopes on MAA-adducted proteins varied depending upon the particular protein. However, when these MAA-adducted proteins were hydrolyzed with Pronase, the concentration of these modified proteins necessary to achieve 50% inhibition of antibody binding in a competitive ELISA fell into a much narrower range of values, indicating that protein hydrolysis equalized the accessibility of the antibody to bind the epitope on these various derivatized proteins. In summary, a cyclic fluorescent adduct of defined structure has been identified as the epitope recognized by our MAA adduct antibody. In addition to this specific adduct, MAA adducts are also comprised of other nonfluorescent products.

Acetaldehyde↗
PubMed1996

Impairment of the asialoglycoprotein receptor by ethanol oxidation.

It is well established that ethanol exposure impairs the process of receptor-mediated endocytosis in hepatic cells, although the molecular mechanism(s) and the physiological consequence(s) of this impairment are unclear. Because addressing these mechanistic questions is difficult in vivo, we have developed a recombinant cell line of hepatic origin capable of metabolizing ethanol. In this study, we have used these recombinant cells, designated HAD cells, to investigate the ethanol-induced impairment to the receptor-mediated endocytosis of the hepatic asialoglycoprotein receptor. Comparing the binding of the ligand asialoorosomucoid in both the parental Hep G2 cells and the recombinant HAD cells, maintained in the presence and absence of ethanol, revealed decreased ligand binding in the HAD cells. This impairment was accentuated by prolonging the ethanol exposure, reaching approximately 40% in both surface and total receptor populations by 7 days. Addition of the alcohol dehydrogenase inhibitor pyrazole to the ethanol-containing medium abolished this impairment, indicating that the decreased binding was a result of the alcohol dehydrogenase-mediated oxidation of ethanol. Furthermore, using antibody specific to the asialoglycoprotein receptor, it was demonstrated that the ethanol-induced impairment in ligand binding was a consequence of decreased ligand binding and not a result of diminished receptor numbers. These results indicated that ethanol oxidation was required for the ethanol-induced impairment in ligand binding, and that the reduced ligand binding was a result of a decrease in the ability of the ligand to bind to the receptor.

Asialoglycoprotein Receptor↗
PubMed1996

Acetaldehyde and malondialdehyde react together to generate distinct protein adducts in the liver during long-term ethanol administration.

Acetaldehyde and the lipid peroxidation-derived aldehyde malondialdehyde (MDA), are reactive compounds that are generated during ethanol metabolism in the liver, and both aldehydes have been shown to be capable of binding to proteins and forming stable adducts. Because similar concentrations of MDA and acetaldehyde can coexist in the liver during ethanol oxidation, protein adduct formation in the presence of both of these aldehydes was studied under both in vitro and in vivo conditions. When proteins were incubated in the presence of both MDA and acetaldehyde, MDA caused a marked and concentration-dependent increase in the stable binding of acetaldehyde to proteins. Maximum stimulation of binding occurred at approximately a fourfold molar excess of MDA relative to acetaldehyde when concentrations of 1.0 mmol/L and 0.1 mmol/L were tested. The formation of highly fluorescent product or products was associated with the MDA stimulation of acetaldehyde binding, indicating that new and distinct products were being generated. These hybrid adducts of MDA and acetaldehyde have been designated as MAA adducts. An affinity-purified polyclonal antibody was produced that specifically recognized MAA epitopes on proteins and did not cross-react with carrier proteins or proteins modified with either acetaldehyde or MDA alone. A quantitative competitive enzyme-linked immunosorbent assay (ELISA) was developed and detected the presence of MAA-modified proteins in liver cytosol from ethanol-fed rats but not in pair-fed controls. Quantification of the data from the competitive ELISA indicated the presence of approximately 75 pmoles protein-bound MAA per milligram liver cytosol proteins of the ethanol-fed animals. These results indicate that acetaldehyde and MDA can react together in a synergistic manner and generate hybrid adducts (MAA-adducts) and further suggest that MAA adducts may represent a major species of adducts formed in the liver during ethanol metabolism in vivo.

Acetaldehyde↗
PubMed1996

Morbidity in patients with posttransplant diabetes mellitus following orthotopic liver transplantation.

It is not well understood whether posttransplant diabetes mellitus (PTDM) following orthotopic liver transplantation (OLTx) alters postoperative morbidity. This study was designed to evaluate this question. All adult patients who received an OLTx between July 1985 and March 1993 (n = 497) were evaluated by retrospective chart review for evidence of PTDM after OLTx. The patients identified with PTDM (n = 26) were case matched with nondiabetic OLTx recipients based on primary liver disease diagnosis, age, gender, date of first OLTx, and survival. Liver synthetic function, number and severity of rejection episodes, graft survival, total number of hospital days within the first year post-OLTx, renal function, and number and type of infection episodes were analyzed to assess differences in morbidity between the PTDM and control patients after OLTx. Of the 497 adult patients who underwent OLTx, 26 (5.2%) were identified as having PTDM within 1 month of discharge. Factors which identified individuals at higher risk for DM after OLTx included higher pre-OLTx fasting blood glucose (P = .04); lower body mass index after OLTx (P = .02); and cyclosporine rather than OKT3 induction (P = .009). Graft survival, synthetic function, and the total number of rejection episodes during the first year were not different between the two groups. The morbidity variables of total number of days in the hospital during the first 12 months, renal function, and type and number of infections were also similar between the two groups. In summary, 5.2% of adult patients developed DM within 1 month of OLTx. Pre-existing insulin resistance, postoperative stress, and immunosuppression medications all likely contribute to the development of overt hyperglycemia after OLTx. Although PTDM can be a consequence of OLTx, it does not have a significant impact on patient outcome in the first year after OLTx.

Adult↗
PubMed1996

Effects of chronic ethanol administration on the endocytosis of cytokines by rat hepatocytes.

The effects of chronic ethanol administration on the endocytosis of three representative cytokines were investigated in isolated rat hepatocytes. When hepatocytes were isolated from rats that were fed an ethanol liquid diet for 12 to 13 weeks, these cells exhibited a decreased ability to internalize and degrade transforming growth factor-alpha, tumor necrosis factor-alpha and interleukin-6, compared with hepatocytes from the pair-fed controls. This impaired endocytosis of all three cytokines was accompanied by significant decreases in the amount of hepatocyte surface-bound cytokine. Changes in cytokine binding to surface receptors and reduced rates of receptor-cytokine complex internalization into the cells seem to be major contributors to defective endocytosis in hepatocytes from the ethanol-fed rats. Impaired hepatocyte endocytosis could lead to altered steady-state levels of cytokines in the liver and modified physiological responses to cytokines. These changes could affect homeostasis among the various cell types in the liver and could contribute to liver dysfunction and injury.

Animals↗
PubMed1995

Establishment of a recombinant hepatic cell line stably expressing alcohol dehydrogenase.

Hepatocytes cultured for extended periods of time lose the ability to express alcohol dehydrogenase and thus, the ability to efficiently oxidize ethanol. Therefore, it has been difficult to investigate the effects of chronic ethanol oxidation by hepatocytes in vitro. To circumvent this problem, we have inserted the coding region of an exogenous alcohol dehydrogenase gene into an hepatic cell line. Using the human hepatocellular carcinoma cell line, Hep G2, we have constructed an hepatic cell line that stably expresses alcohol dehydrogenase. These recombinant cells, termed HAD 73.1 cells, express approximately 40% of the alcohol dehydrogenase activity of freshly isolated rat hepatocytes. When the ethanol metabolizing ability of these cells was directly measured, the results indicated that not only were these cells able to metabolize ethanol at approximately 70% of the rate of freshly isolated rat hepatocytes but acetaldehyde concentrations of up to 50 microM were detected in the medium. Furthermore, the level of acetaldehyde produced during ethanol oxidation was augmented by cyanamide, an inhibitor of acetaldehyde oxidation, while the ability of these cells to metabolize ethanol was inhibited by pyrazole, an inhibitor of alcohol dehydrogenase. These results suggest that this in vitro system will be a valuable tool enabling detailed biochemical studies exploring the effects of chronic ethanol oxidation on the liver and the mechanisms of alcohol-induced hepatic cell injury.

Acetaldehyde↗
PubMed1995

Primary liver cancer and survival in patients undergoing liver transplantation for hemochromatosis.

Cirrhotic patients with hereditary hemochromatosis (HHC) have an increased risk of primary liver cancer (PLC). The purpose of this study was to determine the prevalence of primary liver cancer in patients with HHC undergoing orthotopic liver transplantation (OLT). Five liver transplant centers were surveyed; clinical and pathological data on 37 patients with HHC undergoing OLT were retrospectively collected and analyzed. The diagnosis of HHC was established by a combination of serum transferrin-iron saturation, hepatic iron index (HII), and/or pattern of liver iron staining. The diagnosis of HHC had been unsuspected before OLT in 13 of 37 (35%). Primary liver cancer was found in the explants of 10 of 37 patients (27%) and was unsuspected in 7 of 10 (70%); 8 were hepatocellular carcinoma, and 2 were cholangiocarcinoma; foci of hepatocyte dysplasia were found in 6 additional patients. Mean (+/- SEM) hepatic iron content and HII in 20 patients without prior phlebotomy or bleeding were 17.2 mg/g dry weight (+/- 2.9) and 5.5 (+/- 0.8), respectively. The overall 1-year survival rate after OLT in the 37 HHC patients was 58% (v 55% for HHC patients with PLC). We draw the following conclusions: (1) the diagnosis of HHC is often unsuspected before OLT, and HHC should be evaluated pretransplantation by direct and indirect markers; (2) HHC patients undergoing OLT have a high prevalence of primary liver cancer, the majority being unsuspected; and (3) HHC patients have poorer than average survival after OLT, which cannot be explained solely by the presence of concomitant PLC.

Female↗