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Biomedical subjects

B R Bacon

Publications and source records attributed to B R Bacon.

At least 91 records · Page 5Linked to original sources
PubMed1995

Hepatitis C. Recent advances in understanding and management.

Chronic hepatitis C is a major health issue, affecting up to 1.4% of the US population. A high proportion of hepatitis C virus (HCV) infections are chronic. Significant liver disease (chronic hepatitis that is moderate to severe, fibrosis, or cirrhosis) develops in up to 50% of patients chronically infected with HCV. Progression of the disease is unpredictable but is typically slow and evolves over decades. Viral genotype, level of viremia, severity of liver disease, and hepatic iron content influence the response of chronic hepatitis C to therapy. Standard therapy is with interferon alfa-2b (Intron A), 3 million U given subcutaneously three times a week for 6 months. Forty percent of patients have an initial response to interferon therapy, but only half (or fewer) of these patients maintain a long-term sustained response. New treatment strategies are currently being evaluated; however, none, as yet, has emerged as a significant improvement over standard interferon therapy.

Hepatitis C↗
PubMed1994

Hepatitis C virus. What recent studies can tell us.

Hepatitis C virus (HCV) is responsible for most cases of non-A non-B hepatitis and is primarily spread by a parenteral route, although familial, sexual, and maternal transmission may occur rarely. Second-generation assays and the polymerase chain reaction facilitate detection of HCV infection. The association between HCV infection and hepatocellular cancer is well established, whereas the links between HCV infection and essential mixed cryoglobulinemia, porphyria cutanea tarda, membranoproliferative glomerulonephritis, and idiopathic pulmonary fibrosis remain to be defined more clearly. Standard therapy for chronic HCV infection remains interferon alfa-2b (Intron A), although other agents may have potential. We eagerly await additional clarifying studies.

Chronic Disease↗
PubMed1994

Pathophysiology of iron toxicity.

There are several inherited and acquired disorders that can result in chronic iron overload in humans, and the major clinical consequences are hepatic fibrosis, cirrhosis, hepatocellular cancer, cardiac disease, and diabetes. It is clear that lipid peroxidation occurs in experimental iron overload if sufficiently high levels of iron within hepatocytes are achieved. Lipid peroxidation is associated with hepatic mitochondrial and microsomal dysfunction in experimental iron overload, and lipid peroxidation may underlie the increased lysosomal fragility that has been detected in liver samples from both iron-loaded human subjects and experimental animals. Reduced cellular ATP levels, impaired cellular calcium homeostasis, and damage to DNA may all contribute to hepatocellular injury in iron overload. Long-term dietary iron overload in rats can lead to increased collagen gene expression and hepatic fibrosis, perhaps due to activation of hepatic lipocytes. The mechanisms whereby lipocytes are activated in iron overload remain to be elucidated; possible mediators include aldehydic products of iron-induced lipid peroxidation produced in hepatocytes, tissue ferritin, and/or cytokines released by activated Kupffer cells.

Animals↗
PubMed1994

Nonalcoholic steatohepatitis: an expanded clinical entity.

BACKGROUND/AIMS: In the past, nonalcoholic steatohepatitis has been described mostly in obese women with diabetes. The aim of this study was to describe a series of patients with nonalcoholic steatohepatitis with a different clinical profile. METHODS: The clinical, biochemical, and histological features of 33 patients with nonalcoholic steatohepatitis seen from July 1990 to June 1993 were analyzed. RESULTS: The mean age was 47 years. All patients were antibody to hepatitis C virus-negative. Nineteen of 33 (58%) were men, 20 of 33 (61%) were nonobese, 26 of 33 (79%) had normal glucose levels, and 26 of 33 (79%) had normal lipid levels. Fourteen of 33 (42%) had normal glucose and lipid levels and were not obese. Thirteen of 33 (39%) had pathological increases in fibrosis, 5 of whom had micronodular cirrhosis. Of these 13 with severe, progressive disease, 8 (62%) were women, 8 (62%) were obese, 4 (31%) were diabetic or had an elevated glucose level, and 3 (23%) had hyperlipidemia. Although serum iron studies (transferrin saturation and ferritin) were abnormal in 18 of 31 (58%), no patient had hemochromatosis. CONCLUSIONS: Nonalcoholic steatohepatitis can be a severe, progressive liver disease leading to the development of cirrhosis. It should no longer be considered a disease predominantly seen in obese women with diabetes.

Adult↗
PubMed1994

Determination of hepatic iron concentration in fresh and paraffin-embedded tissue: diagnostic implications.

BACKGROUND/AIMS: Determination of hepatic iron concentration (HIC) is essential for the evaluation of hereditary hemochromatosis. Occasionally, only paraffin-embedded liver biopsy specimens are available, or fresh biopsy specimens have been placed in saline for transport. This study aimed to describe a method for extraction of liver tissue from paraffin blocks, determine the accuracy of measurement of HIC in recovered tissue compared with fresh tissue, and determine the effect of immersion in saline on HIC. METHODS: HIC was measured in both fresh and deparaffinized liver specimens (n = 41). Accurate measurements were defined as either a normal result in both specimens or a result in the deparaffinized specimen that was within 30% of the fresh measurement. RESULTS: Measurements of HIC in fresh and deparaffinized tissue showed an excellent linear relationship (r = 0.95). In deparaffinized samples > or = 0.4 mg, accurate measurements were seen in 24 out of 29 specimens, compared with 6 out of 12 specimens weighing < 0.4 mg (P < 0.01). The hepatic iron index calculated from results in deparaffinized samples > or = 0.4 mg correctly classified all patients. Immersion of fresh biopsy specimens in saline for 1 hour resulted in up to 50% iron loss (P < 0.05). CONCLUSIONS: Accurate measurement of HIC in deparaffinized liver biopsy specimens is possible. Calculation of the hepatic iron index from deparaffinized liver tissue can facilitate diagnosis of hemochromatosis when fresh tissue is not available. Samples should not be transported in saline.

Animals↗
PubMed1994

Oxidant injury to hepatic mitochondria in patients with Wilson's disease and Bedlington terriers with copper toxicosis.

BACKGROUND/AIMS: Copper overload leads to liver injury in humans with Wilson's disease and in Bedlington terriers with copper toxicosis; however, the mechanisms of liver injury are poorly understood. This study was undertaken to determine if oxidant (free radical) damage to hepatic mitochondria is involved in naturally occurring copper toxicosis. METHODS: Fresh liver samples were obtained at the time of liver transplantation from 3 patients with Wilson's disease, 8 with cholestatic liver disease, and 5 with noncholestatic liver disease and from 8 control livers. Fresh liver was also obtained by open liver biopsy from 4 copper-overloaded and 4 normal Bedlington terriers and from 8 control dogs. Hepatic mitochondria and microsomes (humans only) were isolated, and lipid peroxidation was measured by lipid-conjugated dienes and thiobarbituric acid-reacting substances. In humans, liver alpha-tocopherol content was measured. RESULTS: Lipid peroxidation and copper content were significantly increased (P < 0.05) in mitochondria from patients with Wilson's disease and copper-overloaded Bedlington terriers. More modest increases in lipid peroxidation were present in microsomes from patients with Wilson's disease. Mitochondrial copper concentrations correlated strongly with the severity of mitochondrial lipid peroxidation. Hepatic alpha-tocopherol content was decreased significantly in Wilson's disease liver. CONCLUSIONS: These data suggest that the hepatic mitochondrion is an important target in hepatic copper toxicity and that oxidant damage to the liver may be involved in the pathogenesis of copper-induced injury.

Adolescent↗
PubMed1994

Increase in hepatic iron stores following prolonged therapy with ribavirin in patients with chronic hepatitis C.

Ribavirin, an oral nucleoside analogue being evaluated as therapy for chronic hepatitis C, is associated with hemolysis. Other hemolytic conditions are known to be associated with accumulation of iron within the liver. We therefore examined hepatic iron stores before and after 6 to 12 months of therapy with ribavirin in 15 patients with chronic hepatitis C. Although there were no significant changes in serum iron or ferritin levels, hepatic iron staining increased in almost all patients. Using a ranking system to quantitate the amount of hepatic iron staining, we found that the mean rank increased from 3.9 to 8.5 after therapy (p < 0.01). In six patients in whom hepatic tissue was available for determination of hepatic iron, concentrations also increased in all cases from a mean of 826 to 1857 micrograms/g dry weight (p < 0.01). The average rate of iron accumulation in these six patients was approximately 1500 micrograms/g per year. Thus hepatic iron concentrations might enter the range clearly associated with hepatic fibrosis after approximately 15 years of continuous therapy.

Adult↗
PubMed1994

Differential production of TNF by Kupffer cells after phagocytosis of E. coli and C. albicans.

Tumor necrosis factor (TNF) of hepatic origin is thought to play a pivotal role early in the genesis of the septic shock syndrome, regardless of microbial etiology. To determine if production of TNF by Kupffer cells varies with microbial taxonomic class, we measured TNF secretory responses in primary cultures of rat Kupffer cells to numerically equivalent gram-negative bacterial or fungal phagocytic challenges. After a 30-min exposure to media, latex beads, soluble Escherichia coli lipopolysaccharide (LPS; serotype 055:B5), live or Formalin-fixed E. coli (serotype 055:B5), live or Formalin-fixed yeast-phase Candida albicans, or live hyphal-phase Candida, samples of culture supernatant were assessed at 30, 60, 120, and 240 min and at 24 h for TNF bioactivity by L929 cell cytotoxicity. Compared with media and latex bead controls, TNF levels progressively increased for up to 240 min after either LPS and equivalently in live E. coli or Formalin-fixed E. coli groups (P < 0.05). Formalin-fixed yeast-phase and live extracellular hyphal-phase C. albicans failed to stimulate production of TNF at any time point (6.9 +/- 0.7 and 8.7 +/- 0.4 U/ml, respectively, at t = 240 min; P < 0.05 vs. E. coli). In contrast, internalization of live yeast-phase C. albicans with subsequent hyphal formation and growth within Kupffer cells was accompanied by a rise in supernatant TNF levels (14.5 +/- 1.8 U/ml at t = 240 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

TNF-alpha and IL-6 expression in perfused rat liver after intraportal candidemia vs. E. coli or S. aureus bacteremia.

We tested the hypothesis that regulation of tumor necrosis factor-alpha (TNF-alpha) and IL-6 by the liver differs after intraportal challenge with Candida albicans spp. vs. gram-negative or gram-positive bacteria, independent of microbial clearance kinetics or hepatic O2 consumption (VO2). Buffer-perfused rat livers were infected with equivalent inocula (10(9) colony-forming units) of viable Escherichia coli serotype 055:B5 (EC), exotoxin C-producing Staphylococcus aureus (SA), or two strains of yeast phase C. albicans (CA-1 and CA-2). Microbial clearance and circulating cytokine levels were assessed over 180 min while monitoring VO2 and functional parameters, after which organ-based microbial killing, cell-associated TNF-alpha, and cytokine mRNA levels were determined. Compared with saline controls (normal saline solution; NSS), circulating and cell-associated TNF-alpha and TNF-alpha transcripts minimally increased after CA. In contrast, large increases in perfusate TNF-alpha occurred after EC, peaking at 180 min [135 +/- 32 U/ml (mean + SE)], concomitant with rises in cell-associated cytokine and TNF-alpha transcripts (P < 0.01 vs. NSS). Circulating TNF-alpha also rose after SA but neither cell-associated nor mRNA levels exceeded NSS values. There were no pathogen-specific differences in microbial clearance or VO2. IL-6 gene expression paralleled that for TNF-alpha, but IL-6 bioactivity in perfusates was inhibited by TNF-alpha-dependent and -independent mechanisms. We conclude that hepatic TNF-alpha and IL-6 expression are differentially regulated after taxonomically diverse microbial challenges, with E. coli eliciting the strongest and Candida spp. the weakest stimulatory responses.

Animals↗
PubMed1994

Identification and characterization of a receptor for tissue ferritin on activated rat lipocytes.

Hepatic iron overload causes lipocyte activation with resultant fibrogenesis. This study examines whether rat lipocytes express ferritin receptors, which could be involved in paracellular iron movement and in cellular regulation. Lipocytes from normal rat liver were cultured on plastic and incubated with 125I-labeled rat liver ferritin (RLF) +/- a 100-fold excess of either unlabeled RLF or human heart ferritin, human liver ferritin, human recombinant H-ferritin, a mutant human recombinant L-ferritin, or a variety of nonspecific proteins. Specific binding sites for ferritin were demonstrated by displacement of 125I-RLF by RLF (64.5 +/- 4.3%) and by other ferritins (55-60%), but not by recombinant L-ferritin. Scatchard analysis demonstrated a single class of binding sites with a Kd of 5.1 +/- 2.9 x 10(-10) M, maximum binding capacity of 4.7 +/- 1.3 x 10(-12) M, and 5,000-10,000 receptor sites/cell. Ferritin receptor expression was observed only in activated lipocytes. Internalization of RLF was observed within 15 min using FITC-RLF and confocal microscopy. This study demonstrates that (a) activated lipocytes express a specific high affinity ferritin receptor; (b) the binding appears to be dependent on the H-ferritin subunit; and (c) lipocytes internalize ferritin. Expression of ferritin receptors in activated lipocytes suggests that the receptor may either be involved in the activation cascade or may be a marker of activation.

Actins↗
PubMed1994

Hereditary hemochromatosis. Detecting and correcting iron overload.

Hereditary hemochromatosis is a common genetic disorder. A large number of homozygous patients with early disease are asymptomatic, but with early diagnosis and treatment, their life expectancy is normal. The best screening test is determination of the percent saturation of transferrin or the transferrin index. Liver biopsy with measurement of hepatic iron concentration is required for definitive diagnosis. Once the diagnosis is confirmed, treatment by phlebotomy at regular intervals is straightforward.

Bloodletting↗
PubMed1994

Role of free radicals in liver diseases and hepatic fibrosis.

An increased production of free radicals in the liver has been implicated in a variety of liver diseases. Free radicals can damage cellular macromolecules and, therefore, may participate in hepatocellular injury when produced in excess. Strong evidence exists for hepatic free radical production in animal models of iron and copper overload, ethanol consumption, and ischemia-reperfusion. Although less is known about the situation in humans with liver diseases, the available evidence is consistent with the findings in animal experiments. Treatments that reduce free radical production and/or levels have protective effects in hepatic ischemia-reperfusion. Free radical-initiated lipid peroxidation may play a role in hepatic fibrogenesis, perhaps through an effect of aldehydic peroxidation products on Kupffer cells and lipocytes. This hypothesis is supported by the observation that dietary supplementation with vitamin E has a protective effect on carbon tetrachloride-induced hepatic fibrosis. While cellular damage in human liver diseases is probably multifactorial, free radicals may play important roles in initiating and/or perpetuating this damage.

Alcoholic Intoxication↗
PubMed1994

Jejunized colon: a rare complication of carcinoid tumor.

A 23-yr-old female with a history of dyspnea, palpitation, productive cough, occasional hemoptysis, intermittent diarrhea, and abdominal pain was found to have metastatic carcinoid tumor and a "jejunized colon." Carcinoid tumors are relatively rare neoplasms found throughout the gastrointestinal tract, the ovaries, and the lungs. Barium enema showed a normal rectum and a pattern identical to jejunum in the proximal colon. Endoscopic biopsies confirmed the presence of small intestinal mucosa in the colon. Foreshortening of the colon was probably due to a desmoplastic reaction secondary to the carcinoid tumor. Histologic confirmation of these findings has never been described before.

Adult↗
PubMed1993

Hepatic mitochondrial energy production in rats with chronic iron overload.

BACKGROUND: Iron overload results in impaired hepatic mitochondrial oxidative metabolism. The current experiments evaluated the effects of iron overload on enzyme activities in the mitochondrial electron transport chain, on hepatic adenine nucleotide levels, and on hepatocellular oxygen consumption. METHODS: Hepatic iron overload was produced in rats using dietary carbonyl iron. Hepatic adenine nucleotides were assessed after freeze-clamping, mitochondrial enzyme activities and oxygen consumption were measured in isolated mitochondria, and oxygen consumption in isolated hepatocytes was determined. RESULTS: At a mean hepatic iron concentration of 4630 micrograms/g, there were no changes in reduced nicotinamide adenine dinucleotide (NADH)-cytochrome c reductase activity (complex I-III), but there was a 35% reduction in succinate-cytochrome c reductase activity (complex II-III), and a 70% decrease in cytochrome c oxidase activity (complex IV). With mild iron loading (2060 micrograms/g), there was a 28% decrease in hepatic adenosine 5'-triphosphate (ATP) levels with no change in adenosine 5'-diphosphate (ADP) or adenosine 5'-monophosphate (AMP) levels, whereas, at a higher hepatic iron concentration (3170 micrograms/g), there was a 40% reduction in ATP levels, a 22% decrease in ADP levels, with no change in AMP levels. There was a 48% reduction in oxygen consumption in isolated iron-loaded hepatocytes. CONCLUSIONS: Chronic iron overload decreases hepatic mitochondrial cytochrome c oxidase activity, hepatocellular oxygen consumption, and hepatic ATP levels.

Adenosine Diphosphate↗
PubMed1993

A 39-year-old man with chronic hepatitis, elevated serum ferritin values, and a family history of hemochromatosis.

The patient described is a heterozygote for hemochromatosis, and he has chronic hepatitis C. We have hypothesized that, because of chronic viral hepatitis, he could either have an increase in circulating NTBI or he could have up-regulation of hepatocyte TfR expression, perhaps caused by a viral effect on the IRE of TfR mRNA, or a combination of both. Either could result in an increase of his hepatocellular iron uptake, resulting in a redistribution of his total body iron burden (which is in the range seen for HHC heterozygotes) and, in effect, "concentrating" the iron in his liver, thus simulating homozygous HHC. It is likely that there are interrelationships between hepatic iron concentration, hepatocellular iron metabolism, and chronic viral hepatitis. Understanding of these interrelationships may be important in the understanding of some of the fundamental mechanisms of viral growth and replication and hepatocellular injury. A clearer understanding of these interactions is necessary to diagnose the cause of liver disease accurately in patients such as this one.

Adult↗