Biomedical subjects
B R Bacon
Publications and source records attributed to B R Bacon.
Increased 4-hydroxynonenal levels in experimental alcoholic liver disease: association of lipid peroxidation with liver fibrogenesis.
The precise role of lipid peroxidation in the pathogenesis of alcoholic liver disease is still being debated. To explore the issue, this study was undertaken to investigate the status of lipid peroxidation, antioxidants and prooxidants at two discrete stages of experimental alcoholic liver disease. Male Wistar rats were intragastrically fed a high-fat diet plus ethanol for 5 or 16 wk (the duration that resulted in initiation of centrilobular liver necrosis or liver fibrosis, respectively). Lipid peroxidation was assessed in isolated microsomes and mitochondria with three parameters: malondialdehyde equivalents as determined by thiobarbituric acid assay, conjugated diene formation and 4-hydroxynonenal as a 2,4-dinitrophenylhydrazone derivative. To assess antioxidant systems, hepatic concentrations of glutathione, methionine and alpha-tocopherol were determined. The concentration of nonheme iron, a known prooxidant, was also measured. At wk 5, centrilobular liver necrosis was already evident in the ethanol-fed animals, with two- or threefold increases in plasma AST and ALT levels. At this stage, neither malondialdehyde equivalents nor conjugated diene values were elevated, and the 4-hydroxynonemal level was below 0.2 nmol/mg protein. Hepatic concentrations of methionine and alpha-tocopherol in these animals were increased two- and threefold, respectively, whereas the reduced glutathione level remained unchanged. When alcoholic liver disease had progressed to perivenular or bridging fibrosis at wk 16, all three parameters of lipid peroxidation showed consistent increases that were accompanied by significant reductions in the hepatic glutathione and methionine levels. Interestingly, the control animals pair-fed with the high-fat diet also had significantly elevated 4-hydroxynonenal levels at wk 16 compared to the wk 5 level.(ABSTRACT TRUNCATED AT 250 WORDS)
Measurements of iron status in patients with chronic hepatitis.
Eighty patients with chronic viral hepatitis were screened for evidence of iron overload. Elevated serum iron values were noted in 36% of cases; serum ferritin values were above normal in 30% of men and 8% of women. Twenty-eight additional patients with chronic hepatitis for whom liver tissue was available for determination of iron content were evaluated to study the significance of iron overload in association with chronic hepatitis. Although 46% had elevated serum iron, ferritin, or transferrin-saturation levels, the hepatic iron concentration was elevated in only four cases, and the hepatic iron index was in the range for hereditary hemochromatosis (greater than 2.0) in only two of these. Serum aspartate aminotransferase activities correlated with serum ferritin levels in these patients, suggesting that ferritin and iron levels were increased in serum because of their release from hepatocellular stores associated with necrosis. Thus, in patients with chronic hepatitis in whom hereditary hemochromatosis is suspected, a liver biopsy should be performed with quantitation of hepatic iron and calculation of the hepatic iron index to confirm the diagnosis.
Valproate use associated with persistent hyperammonemia and mitochondrial injury in a child with Down's syndrome.
Valproate is a commonly prescribed anticonvulsant drug that may cause potentially fatal hepatotoxicity, bone-marrow toxicity, and pancreatitis. Toxicity usually resolves, though, after discontinuation of the medication. We report a 9-year-old boy who had Down's syndrome and who developed valproate-associated bone marrow toxicity, and hepatotoxicity that persisted greater than 2 years after discontinuation of valproate therapy. Three years after starting valproate, he developed erythrocyte aplasia with a severe, normochromic, macrocytic anemia requiring several blood transfusions. Several months later while still receiving valproate, he developed progressive hyperammonemia and decreased hepatic synthetic function. The macrocytic anemia resolved and hepatic synthetic function improved after discontinuation of valproate therapy. However, hyperammonemia, steatosis, mitochondrial injury, and marked hepatic iron accumulation persisted greater than 2 years after the valproate was discontinued. The persistent hyperammonemia was responsive to lactulose therapy. A decrease in hepatic iron content by serial phlebotomies did not result in any improvement in the hyperammonemia or hepatic synthetic function. This is the first report of persistent hyperammonemia and hepatic mitochondrial injury after valproic acid therapy.
Unsuspected portal vein thrombosis associated with temporizing sclerotherapy prior to orthotopic liver transplantation.
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Endoscopic retrograde sphincterotomy in swine.
Endoscopic retrograde sphincterotomy was performed on four sedated pigs, ages 3-4 months, using a standard human duodenoscope and papillotome. Sphincterotomies, 1 cm in length, were well-tolerated, and all animals recovered promptly, spontaneously regained gastrointestinal function, and gained weight. The first three animals were sacrificed after one week, and autopsy revealed no complications. The fourth animal was sacrificed immediately following the procedure, and no evidence of perforation was found. These observations demonstrate that the pig is a valid experimental model for endoscopic sphincterotomy. Its use in training is limited by technical and anatomic differences from humans. Potential uses of this technique in research are discussed.
Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes [corrected].
The purpose of these experiments was to determine whether chronic dietary iron overload causes impairment of hepatic mitochondrial and/or microsomal calcium sequestration. Experimental iron overload was produced by feeding three groups of rats a chow diet supplemented with 3.0% (wt/wt) carbonyl iron for up to 8 weeks achieving graded increases in hepatic iron concentrations ranging from 1360 to 3170 micrograms/g. At low levels of iron overload, there were no changes in mitochondrial oxidative metabolism or calcium sequestration, whereas at moderate and high degrees of iron loading, both of these parameters were significantly reduced. In contrast, there were significant decreases in microsomal cytochrome P450 levels and microsomal calcium sequestration at all three levels of iron loading. These abnormalities occurred at hepatic iron concentrations at which the authors have previously found evidence of hepatic organelle lipid peroxidation. These alterations in organelle calcium sequestration may impair intracellular calcium homeostasis in the liver and contribute to subsequent cellular injury.
Managing chronic hepatitis. Recent advances in diagnosis and treatment.
A variety of effective therapies are now available for chronic hepatitis of various causes. Most patients with autoimmune chronic active hepatitis respond to immunosuppressive therapy, and those with Wilson's disease respond to copper-chelating therapy. Patients with drug-induced chronic hepatitis improve with cessation of the medication. About 30% to 40% of patients with chronic hepatitis B infection respond to interferon alfa, as do about 50% of those with chronic hepatitis C infection.
Pleuropulmonary complications of endoscopic variceal sclerotherapy.
The most common pulmonary complication of EVS is pleural effusion. The most clinically significant pulmonary complication of EVS is delayed perforation with formation of esophagopleural or esophagobronchial fistula. Pneumonia, empyema, pulmonary infarction, and atelectasis can also occur. Endoscopic variceal sclerotherapy probably does not cause ARDS, but that issue remains unsettled. Transient relative pulmonary hypertension during EVS is probably of no clinical significance, but caution is urged when sclerosing varices in a patient with borderline right heart function.
Delayed subcapsular hematoma after percutaneous liver biopsy as a manifestation of warfarin toxicity.
Guidelines for the management of patients receiving chronic anticoagulation therapy who require liver biopsy are not clearly defined. In patients with normal coagulation, liver biopsy is a relatively safe procedure with a morbidity of less than 0.1% and a mortality of less than 0.01%. We report a patient with a prosthetic aortic valve who developed a large subcapsular hematoma 12 days after a percutaneous liver biopsy as a consequence of warfarin toxicity. Based on the experience with this patient, reinstitution of anticoagulant therapy should be avoided for at least 72 h after a percutaneous liver biopsy. Intravenous heparin should be resumed first, and warfarin added if no bleeding has occurred after an additional 48-72 h. The prothrombin time should be maintained at 1.5 times the baseline.
Incidental microvesicular steatosis due to valproic acid anticonvulsant therapy.
Valproic acid has been implicated in at least 100 cases of fatal acute liver failure. Most cases have occurred in patients less than 10 yr old; however, at least seven have involved adults. Microvesicular steatosis has been uniformly observed, but its incidence in less severe liver disease and in asymptomatic patients receiving valproate is unknown. We report two patients receiving maintenance valproate, one with resolving acute hepatitis C and the other with chronic persistent hepatitis C, with incidental microvesicular steatosis demonstrated on oil-red O stains. We conclude that microvesicular steatosis does not necessarily signify hepatotoxicity in patients on chronic valproic acid, and should not lead to discontinuation of the drug until other causes of acute or chronic liver disease have been excluded.
Chylous ascites due to sarcoidosis.
A 33-yr-old black female with systemic sarcoidosis developed chylous ascites. A CT scan showed extensive mesenteric lymphadenopathy. At laparotomy, the mesenteric and para-aortic lymph nodes were enlarged and diffusely matted. Histologically, normal lymph node morphology was virtually replaced with noncaseating granulomas. Corticosteroids and dietary manipulations were unsuccessful in managing the ascites, and repeated large-volume paracentesis was necessary to provide symptomatic treatment. This is the first reported case of chylous ascites caused by sarcoidosis.
Hepatic mitochondrial malondialdehyde metabolism in rats with chronic iron overload.
Peroxidative decomposition of mitochondrial membrane phospholipids with subsequent mitochondrial dysfunction is a postulated mechanism of liver cell injury in parenchymal iron overload. Malondialdehyde is formed when polyunsaturated fatty acids of membrane phospholipids undergo peroxidative decomposition, and it is metabolized by aldehyde dehydrogenase. We studied mitochondrial metabolism of malondialdehyde in rats with chronic dietary iron overload. Hepatic malondialdehyde concentrations were significantly increased in iron-loaded livers, and mitochondrial respiratory control ratios using glutamate as a substrate were decreased by 47% largely owing to reductions in state 3 respiration. When exogenous malondialdehyde was added to mitochondrial fractions, there was significantly less metabolism of malondialdehyde in mitochondria of iron-loaded livers as compared with controls. In addition, there was a 28% decrease in mitochondrial aldehyde dehydrogenase in iron-loaded livers but no change in cytosolic aldehyde dehydrogenase. Increased hepatic malondialdehyde in chronic iron overload may result from a combination of increased production and decreased metabolism of malondialdehyde, both of which may be due to iron-induced mitochondrial lipid peroxidation.
The pathology of hepatic iron overload: a free radical--mediated process?
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Increased prooxidant action of hepatic cytosolic low-molecular-weight iron in experimental iron overload.
In the iron-loaded liver there may be an increase in the putative intracellular transit pool of iron, components of which could be catalytically active in stimulating lipid peroxidation. To study the levels of low-molecular-weight, catalytically active iron in the liver, cytosolic ultrafiltrates were tested in an assay containing rat liver microsomes and NADPH. Malondialdehyde production was used as an index of lipid peroxidation. This assay system was sensitive enough to detect 0.25 mumol/L ferrous iron; progressive but non-linear increases in malondialdehyde were produced as the iron concentration was increased to 5 mumol/L. Ultrafiltrates from hepatic cytosol of iron-loaded rats had greater prooxidant action than did those from controls. When added to the assay, deferoxamine, an iron chelator, completely suppressed the prooxidant action of hepatic ultrafiltrates, showing that this activity is iron-dependent. Deferoxamine administered intraperitoneally to control animals at a dose of 1 gm/kg completely inhibited the prooxidant effect of hepatic ultrafiltrates prepared from rats killed after 1, 2 and 3 hr. Partial inhibition was observed at 4 hr; by 6 hr the inhibitory effect of deferoxamine was completely lost. Administration of deferoxamine (1 gm/kg intraperitoneally, 1 hr before killing) completely inhibited the prooxidant action of hepatic ultrafiltrates in moderately iron-loaded rats and controls but had no protective effect in heavily iron-loaded rats. These results support the concept that iron overload results in an increase in a hepatic cytosolic pool of low-molecular-weight iron that is catalytically active in stimulating lipid peroxidation. This pool can be chelated transiently in vivo by deferoxamine in moderate, but not heavy, iron overload.
Prevention of hepatocyte injury and lipid peroxidation by iron chelators and alpha-tocopherol in isolated iron-loaded rat hepatocytes.
These experiments were performed to characterize the relationship between lipid peroxidation and hepatocyte viability in iron overload. Hepatocytes were isolated from rats with chronic dietary iron overload and the effects of in vitro iron chelation on lipid peroxidation, cell viability and ultrastructure were studied over a 4-hr incubation period. Cell viability was significantly reduced at 3 and 4 hr in iron-loaded hepatocytes compared with controls and was preceded by an increase in iron-dependent lipid peroxidation. Similarly, extensive degenerative ultrastructural changes were observed in iron-loaded hepatocytes compared with controls after 4 hr of incubation. In vitro iron chelation with either deferoxamine or apotransferrin protected against lipid peroxidation, loss of viability and ultrastructural damage in iron-loaded hepatocytes. The addition of an antioxidant, alpha-tocopherol, also protected against lipid peroxidation and preserved cell viability over a 4-hr incubation. The protective effects of iron chelators and alpha-tocopherol support a strong association between iron-dependent lipid peroxidation and hepatocellular injury in iron overload.
Iron and the liver: genetic hemochromatosis and other hepatic iron overload disorders.
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Hepatologic considerations in patients with parenchymal liver disease undergoing surgery.
Patients with liver disease requiring surgical procedures are at increased perioperative risk. In addition, the deleterious effect of anesthesia on hepatocellular function, altered drug pharmacokinetics, aberrant hemostasis, postoperative encephalopathy and infection, with multiorgan failure, all contribute to perioperative morbidity and mortality. Although limited by the lack of widely accepted quantitative liver function tests, preoperative evaluation and risk assessment is imperative. Acute viral hepatitis, alcoholic hepatitis, refractory coagulopathy, Child's class C cirrhosis, and emergent surgery are major risk factors predictive of a poor outcome. In addition, elective abdominal surgical procedures should be avoided in potential candidates for orthotopic liver transplantation. Identification and correction of reversible risk factors via meticulous preoperative definition of the etiology, chronicity, and severity of the patient's liver disease within the confines of surgical urgency is the goal of the preoperative hepatology consultation.