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B R Bacon

Publications and source records attributed to B R Bacon.

At least 37 records · Page 2Linked to original sources
PubMed2000

Histological evaluation of iron in liver biopsies: relationship to HFE mutations.

OBJECTIVE: Hepatic iron overload is observed in many forms of chronic liver disease. Hereditary hemochromatosis (HH) results in hepatic iron overload and is associated with 2 missense mutations in the HFE gene. The aim of this study was to define the usefulness of the histological pattern of iron deposition in determining the probability of an iron-loaded patient having HFE-related iron overload. METHODS: This study assessed liver biopsies containing stainable iron from 103 patients with various liver diseases; clinical information included hepatic iron concentration and HFE genotype (C282Y, H63D). The biopsies were evaluated using a reproducible histological scoring system for iron deposition. Three separate components of histological iron deposition were recorded: 1) pattern (primarily hepatocellular with a zonal gradient, or reticuloendothelial without an obvious zonal gradient), 2) pattern score to denote the extent of iron within the acinus, and 3) quantitation grade of iron granules within affected hepatocytes. RESULTS: The predominantly hepatocellular pattern (HH pattern) was observed in 72 biopsies of which only 42 were from patients homozygous for the C282Y mutation, indicating that this pattern alone cannot be used as a surrogate marker for HH genotype. The predominantly reticuloendothelial pattern (non-HH pattern) was observed in the remaining 31 patients, none of whom was compound heterozygous or homozygous for the C282Y mutation (negative predictive value: 100%). Thus, the non-HH, reticuloendothelial pattern reliably predicts the absence of homozygosity for the C282Y mutation. CONCLUSIONS: The use of histological evaluation for iron deposition is simple, assists in expanding information communicated from histopathologic observations, and may be clinically useful in determining the necessity of further evaluation of HFE genotype in subjects with histological evidence of hepatic iron overload.

Adult↗
PubMed2000

Cell surface expression of HFE protein in epithelial cells, macrophages, and monocytes.

BACKGROUND AND OBJECTIVE: Most patients with hereditary hemochromatosis are homozygous for a Cys282AETyr mutation in the HFE gene. This mutation has been shown to impair the association of the HFE gene product with b(2)-microglobulin and to prevent its cell surface presentation in transfected COS-7 and 293 cells. This study was performed to examine the expression of HFE protein in epithelial cells, macrophages, and circulating leukocytes obtained from normal subjects and patients with hereditary hemochromatosis. DESIGN AND METHODS: Antisera against two different peptides of the HFE protein were used to immunostain tissue sections and isolate granulocytes, lymphocytes and monocytes. RESULTS: Immunocytochemical staining showed that the HFE protein is expressed in gastric epithelial cells, tissue macrophages, and circulating monocytes and granulocytes. The cell surface associated signal, which was seen in normal gastric epithelial cells, monocytes and macrophages, was also present in C282Y mutant cells from patients with hereditary hemochromatosis, although at apparently reduced amounts in these cells. INTERPRETATION AND CONCLUSIONS: From these studies, it is clear that the C282Y mutation reduces but does not completely prevent presentation of the HFE protein on the cell surface of human monocytes, tissue macrophages, and gastric epithelial cells.

Amino Acid Substitution↗
PubMed1999

Available options for treatment of interferon nonresponders.

In the great majority of patients, hepatitis C virus (HCV) infection is not self-limiting. Approximately 70% to 85% of patients exposed to HCV will go on to develop chronic hepatitis. Among those who undergo treatment with interferon alpha, only 15% to 20% can be expected to respond to a 12- to 18-month course of therapy. With the addition of ribavirin to interferon monotherapy, the likelihood of sustained response (defined as normal alanine aminotransferase levels and negative HCV RNA persisting 6 months after the end of therapy) increases to approximately 40%. The fact remains, however, that there is still a substantial proportion of patients who will fail to respond to treatment. Without viral eradication, cirrhosis and hepatocellular carcinoma persist as long-term risks. Several options are available for the treatment of patients who fail to respond to interferon monotherapy. These include interferon dose escalation, whether by administering higher doses or administering them more frequently; changing to a different form of interferon; retreatment with a combination of interferon and ribavirin; adjunctive therapies, of which the best studied is phlebotomy to decrease hepatic iron stores; use of long-term, low-dose "maintenance"-type therapy; and watchful waiting with frequent follow-up. In the absence of long-term, large-scale clinical trials to support these modalities, physicians must exercise their best clinical judgment and individualize treatment to suit the patient's condition, needs, and preferences.

Antiviral Agents↗
PubMed1999

HFE genotype in patients with hemochromatosis and other liver diseases.

BACKGROUND: Hereditary hemochromatosis is a common inherited disorder of iron metabolism. The gene HFE, which contains two missense mutations (C282Y and H63D), was recently identified. OBJECTIVE: To determine how HFE genotyping for the C282Y and H63D mutations contributes to the diagnosis of hemochromatosis and to determine the prevalence of HFE mutations in a group of patients with liver disease. DESIGN: Cross-sectional study. SETTING: Academic medical center. PATIENTS: 66 patients with hereditary hemochromatosis and 132 referred patients with other liver diseases. MEASUREMENTS: At initial diagnosis, fasting transferrin saturation, ferritin level, routine chemistry panel, and complete blood count were determined. Percutaneous liver biopsy was done on all patients for histologic analysis and measurement of hepatic iron concentration and hepatic iron index. HFE genotyping for the C282Y and H63D mutations was done on all patients by using genomic DNA samples. RESULTS: Of the 66 patients with hemochromatosis diagnosed on the basis of serum iron studies and liver biopsy findings, 60 (91%) were C282Y homozygotes, 2 (3%) were compound heterozygotes, 1 (1.5%) was a C282Y heterozygote, 2 (3%) were H63D heterozygotes, and 1 (1.5%) was negative for both mutations. Of the 132 patients with liver disease, 6 (5%) were C282Y homozygotes, 8 (6%) were compound heterozygotes, 6 (5%) were C282Y heterozygotes, 5 (4%) were H63D homozygotes, 20 (15%) were H63D heterozygotes, and 87 (66%) were negative for both mutations. All 66 C282Y homozygotes had an elevated hepatic iron concentration, and 65 of the 66 patients (98%) had a transferrin saturation of at least 45%. Ten of the 66 patients (15% [95% CI, 7.5% to 26%]) had a hepatic iron index less than 1.9 mmol/kg per year; hemochromatosis was not suspected in 6 of the 10 patients before genotyping. Cirrhosis or substantial hepatic fibrosis was not seen in any (0% [CI, 0% to 18%]) of the 19 patients younger than 40 years of age who were homozygous for the C282Y mutation. CONCLUSIONS: All 66 patients homozygous for the C282Y mutation of HFE had an elevated hepatic iron concentration, but approximately 15% of these patients did not meet a previous diagnostic criterion for hemochromatosis (hepatic iron index > 1.9 mmol/kg per year). Determination of HFE genotype is clinically useful in patients with liver disease and suspected iron overload and may lead to identification of otherwise unsuspected C282Y homozygotes.

Adult↗
PubMed1999

Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1.

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by tissue iron deposition secondary to excessive dietary iron absorption. We recently reported that HFE, the protein defective in HH, was physically associated with the transferrin receptor (TfR) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin-bound iron from plasma by duodenal crypt cells, leading to up-regulation of transporters for dietary iron. Here, we tested the hypothesis that HFE-/- mice have increased duodenal expression of the divalent metal transporter (DMT1). By 4 weeks of age, the HFE-/- mice demonstrated iron loading when compared with HFE+/+ littermates, with elevated transferrin saturations (68.4% vs. 49.8%) and elevated liver iron concentrations (985 micrograms vs. 381 micrograms). By using Northern blot analyses, we quantitated duodenal expression of both classes of DMT1 transcripts: one containing an iron responsive element (IRE), called DMT1(IRE), and one containing no IRE, called DMT1(non-IRE). The positive control for DMT1 up-regulation was a murine model of dietary iron deficiency that demonstrated greatly increased levels of duodenal DMT1(IRE) mRNA. HFE-/- mice also demonstrated an increase in duodenal DMT1(IRE) mRNA (average 7.7-fold), despite their elevated transferrin saturation and hepatic iron content. Duodenal expression of DMT1(non-IRE) was not increased, nor was hepatic expression of DMT1 increased. These data support the model for HH in which HFE mutations lead to inappropriately low crypt cell iron, with resultant stabilization of DMT1(IRE) mRNA, up-regulation of DMT1, and increased absorption of dietary iron.

Animals↗
PubMed1999

Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum.

In hereditary hemochromatosis (HH), intestinal absorption of dietary iron is increased, leading to excessive iron accumulation in tissues and resultant organ damage. The HFE protein, which is defective in HH, normally is expressed in crypt enterocytes of the duodenum where it has a unique, predominantly intracellular localization. In placenta, the HFE protein colocalizes with and forms a stable association with the transferrin receptor (TfR), providing a link between the HFE protein and iron transport. In the present study, we examined the relationship of the HFE protein to the TfR in enterocytes of the human duodenum and measured the uptake of transferrin-bound iron and ionic iron by isolated crypt and villus enterocytes. Immunocytochemistry showed that the HFE protein and TfR both are expressed in the crypt enterocytes. Western blots showed that, as was the case in human placenta, the HFE protein in crypt enterocytes is physically associated with the TfR and with beta2-microglobulin. The crypt cell fraction exhibited dramatically higher transferrin-bound iron uptake than villus cells. On the other hand, the villus cells showed 2-3 times higher uptake of ionic iron than crypt cells. We propose that the HFE protein modulates the uptake of transferrin-bound iron from plasma by crypt enterocytes and participates in the mechanism by which the crypt enterocytes sense the level of body iron stores. Impairment of this function caused by HFE gene mutations in HH could provide a paradoxical signal in crypt enterocytes that programs the differentiating enterocytes to absorb more dietary iron when they mature into villus enterocytes.

Biological Transport↗
PubMed1999

Effects of iron loading on pathogenicity in hepatitis C virus-infected chimpanzees.

Elevated iron levels have been associated with raised serum alanine transaminase (ALT) levels in hepatitis C virus (HCV)-infected humans. However, it is not clear if HCV infection causes increased iron accumulation by the liver or if the severity of HCV infection is actually worsened by higher iron levels in the host. To better understand the relationship between iron and persistent HCV infections, we examined the effect of excess dietary iron on disease severity in HCV-infected chimpanzees. Iron was supplemented in the diets of four HCV-infected and two uninfected chimpanzees for 29 weeks to achieve iron loading. Iron loading was confirmed by increases in serum iron levels, percentages of transferrin saturation, ferritin levels, elevations in hepatic iron concentration (HIC), and by histological examination. The majority of HCV-infected chimpanzees had higher iron levels before iron feeding than the uninfected animals. Although various degrees of iron loading occurred in all chimpanzees, HCV-infected animals exhibited increased loading in comparison with uninfected animals. The effects of iron loading on HCV disease expression was determined by comparing disease parameters during an extended baseline period before iron loading with the period during iron loading and immediately following iron loading. Iron loading did not influence the viral load, but did exacerbate liver injury in HCV-infected chimpanzees, as evidenced by elevated ALT and histological changes. Because all chimpanzees on high iron diets experienced iron loading, but pathological effects were only observed in HCV-infected chimpanzees, HCV infection appears to increase the susceptibility of the liver to injury following iron loading. These results confirm and extend previous observations made in human populations and serve to further validate the chimpanzee model of chronic hepatitis C.

Alanine Transaminase↗
PubMed1999

Hepatic iron and nonalcoholic fatty liver disease.

Increased iron is suspected to enhance hepatic injury associated with nonalcoholic fatty liver disease (NAFL). We evaluated the impact of iron accumulation on the outcome of NAFL. Patients with NAFL were identified from our database. Twenty-two clinicodemographic and 19 pathological features were available for each patient. Histological staining (Perls' Prussian blue), hepatic iron concentration (HIC), and hepatic iron index (HII) were determined. Data on follow-up, mortality, and cause of death were analyzed. In 65 patients with available liver biopsy blocks, HIC and HII were 1,171 +/- 717 microgram/g dry weight and 0.43 +/- 0.30 micromol/g/yr, respectively. Males had more iron accumulation (HIC: 1,514 +/- 836 vs. 859 +/- 389, P =.0001; and HII: 0.58 +/- 0.35 vs. 0.29 +/- 0.16, P =.0001). In type II diabetics, both HIC (977 +/- 769 vs. 1,301 +/- 659; P <.05) and HII (0.30 +/- 0.23 vs. 0.52 +/- 0.32; P <.05) were lower. Iron accumulation was not related to other variables analyzed. Increased iron was not seen in those with higher grades of fibrosis or other pathological features associated with the aggressive form of NAFL (hepatocyte necrosis, fibrosis, ballooning degeneration, and Mallory hyaline). Iron accumulation was not associated with increased overall mortality, liver-related mortality, or development of cirrhosis. In summary, in most patients with NAFL, significant iron accumulation is not seen. Additionally, in our series of patients with NAFL, iron is not associated with poor clinical or pathological outcomes.

Adult↗
PubMed1999

Hereditary hemochromatosis in liver transplantation.

A candidate gene, HFE, was recently described in patients with hereditary hemochromatosis (HH) and found to contain a missense mutation leading to a cysteine to tyrosine substitution (C282Y). A second mutation, H63D, was also found in the gene. This study was undertaken to determine the HFE genotype in liver transplant recipients clinically diagnosed with HH and those incidentally found to have increased iron deposition in their explanted livers and to evaluate whether biochemical or histological hepatic iron indices (HIIs) correlated with homozygosity for the C282Y mutation. We identified 15 patients clinically diagnosed with various liver disorders other than HH who had increased liver iron deposits among 918 adult patients who underwent liver transplantation from 1988 to 1995. Four additional patients were clinically diagnosed as having HH. Archival explant liver tissue was evaluated for the histological HII according to the method of Deugnier et al, in which an index greater than 0.15 suggests homozygosity for HH. The HII was computed according to established methods, with a value greater than 1.9 suggesting homozygosity for HH. A portion of liver tissue was subjected to DNA genotyping using polymerase chain reaction-amplified products. Two of 4 patients with clinically suspected HH were homozygous for C282Y, and 2 patients had neither mutation. One of the 15 patients not suspected to have HH was a C282Y homozygote, 1 was a C282Y heterozygote, 6 were H63D heterozygotes, and 7 had neither mutation. The histological HII was consistent with HH in 13 patients, whereas the HII was consistent with HH in 6 patients. Thus, in patients with end-stage liver disease, despite fulfilling the established clinical criteria for HH using biochemical and histological parameters, only a minority of patients were homozygous for the C282Y mutation. Hepatic iron overload may result from other causes, and in end-stage liver disease, an elevated HII may not accurately predict HH. Other factors that either control or lead to iron absorption may explain iron overload in these patients.

Adult↗
PubMed1999

Long-term follow-up after liver transplantation in patients with hepatic iron overload.

Patients with hepatic iron overload who undergo orthotopic liver transplantation (OLT) have a worse 1-year survival than those who undergo transplantation for other indications; the long-term outcome in this population is unknown. The purpose of this study is to report long-term follow-up after OLT in a cohort of patients with hepatic iron overload. Five liver transplant centers in the United States reported follow-up data on 37 patients receiving a first liver transplant who had severe hepatic iron overload in their native livers. Kaplan-Meier 5-year survival among these patients was compared with survival data from all age-matched liver transplantations reported to the United Network for Organ Sharing (UNOS) over the same time period (1987 to 1993). The 5-year survival rate after OLT was 40% in the hepatic iron overload group compared with an overall survival rate of 62% for all patient groups from the UNOS registry (P =.0009). Although sepsis was the cause of 53% of all deaths occurring within the first year after OLT, cardiac complications accounted for 50% of the late mortality in patients with hepatic iron overload. In conclusion, long-term survival after OLT is significantly decreased in patients with hepatic iron overload. Infectious and cardiac complications are the most common causes of death in these patients. Further studies are needed to define the relationship between hepatic iron overload and mortality and to examine the effect of iron depletion on outcome after OLT in this patient population.

Cause of Death↗
PubMed1999

Liver transplantation in patients with chronic hepatitis C and alcoholism.

We evaluated the contribution of alcohol abuse to liver failure among patients undergoing liver transplantation by reviewing their records for alcohol consumption, hepatitis serology, and outcome. Anti-HCV was present in the serum of 42 patients (39%), while 35 had consumed more than 80 g/day of alcohol for at least 10 years, allowing patients to be divided into four groups: group I, hepatitis C alone (N = 31); group II, alcoholic liver disease alone (N = 24); group III, both hepatitis C and alcoholism (N = 11); and group IV, liver failure due to other causes (N = 41). Patients were followed for a mean of 29 months after transplantation (range 0-66). Twenty-eight (26%) died during follow up, while 11 (10%) required retransplantation. There were no other significant differences in patient or graft survival among patients in the four groups. Patients with both alcoholism and chronic hepatitis C comprise a large proportion of those undergoing liver transplantation and appear to do as well as those with other causes of liver failure, at least in the short term.

Adult↗
PubMed1999

An in vitro model for the study of phagocytosis of damaged hepatocytes by rat Kupffer cells.

AIMS/BACKGROUND: One function of Kupffer cells is the phagocytosis of nonviable hepatocytes. Our aims were to develop a model for phagocytosis of damaged hepatocytes by rat Kupffer cells in vitro, and to characterise prostaglandin E2 (PGE2), prostacyclin (PGI), and tumour necrosis factor-alpha (TNF) production in this model. METHODS: Kupffer cells were incubated alone or with damaged hepatocytes for up to 18 h, then washed and cultured for up to 66 h. To compare mediator responses produced during inert particle phagocytosis, Kupffer cells were also incubated with latex beads. RESULTS: Phagocytic uptake of hepatocyte debris was confirmed in at least 50% of Kupffer cells. A dissociation between TNF and PGI responses was found for both latex beads and damaged hepatocytes, such that a TNF secretory response was not triggered by either stimulus whereas PGI production was increased for both. Although phagocytosis of beads increased PGE2 production, phagocytosis of hepatocytes did not. CONCLUSIONS: Phagocytosis of damaged hepatocytes by Kupffer cells results in the production of PGI but not PGE2 or TNF.

Animals↗
PubMed1999

Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions.

OBJECTIVE: Steatohepatitis is a morphological pattern of liver injury that may be seen in alcoholic or nonalcoholic liver disease. This pattern may occur with obesity, diabetes, the use of certain drugs, or the cause may be idiopathic. The well-recognized histopathological features of nonalcoholic steatohepatitis (NASH) include hepatocellular steatosis and ballooning, mixed acute and chronic lobular inflammation, and zone 3 perisinusoidal fibrosis. Currently, there are no systems for grading necroinflammatory activity or for staging fibrosis as exist for various other forms of chronic liver disease. The purpose of this study was to develop such a grading and staging system and was based on review of liver biopsies from 51 patients with nonalcoholic steatohepatitis from Saint Louis University Health Sciences Center. METHODS: For determination of grade, 10 histological variables of activity were initially analyzed; an overall impression of mild, moderate, and severe was made and the variables considered to be most significant were used to develop the necroinflammatory grade. RESULTS: The histological lesions considered to be significant were: steatosis, ballooning, and intra-acinar and portal inflammation. A staging score was developed to reflect both location and extent of fibrosis. The fibrosis score was derived from the extent of zone 3 perisinusoidal fibrosis with possible additional portal/periportal fibrosis and architectural remodeling. Fibrosis stages are as follows: Stage 1, zone 3 perisinusoidal fibrosis; Stage 2, as above with portal fibrosis; Stage 3, as above with bridging fibrosis; and Stage 4, cirrhosis. CONCLUSION: We propose a grading and staging system that reflects the unique histological features of nonalcoholic steatohepatitis.

Biopsy↗
PubMed1999

Intracellular signaling pathways in stellate cell activation.

Pathological fibrogenesis in the liver is mediated by activated stellate cells. These cells have a myofibroblastic phenotype with the ability to proliferate and synthesize large quantities of extracellular matrix components. A number of factors have been proposed to initiate and perpetuate the fibrogenic process in stellate cells, including inflammatory cytokines, alterations in the extracellular matrix, growth factors, and oxidative stress. Some recent research has focused on the intracellular signaling pathways that are stimulated by these factors in stellate cells, including mitogen-activated protein kinases, phosphatidylinositol 3-kinase, focal adhesion kinase, and protein kinase C. This paper will summarize the experimental evidence that implicates these pathways in stellate cell activation, focusing on the effects of exposure to platelet-derived growth factor, tumor necrosis factor-alpha, and fibronectin. Implications for alcohol-induced hepatic fibrosis and future directions for research will also be discussed.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMed1999

New knowledge of genetic pathogenesis of hemochromatosis and Wilson's disease.

Discovery of the gene for WD has greatly enhanced our understanding of this disorder at the cellular level and has set the stage for future testing of new modes of therapy. Improvements in analytic methods for detecting mutations in genomic DNA will someday enable a rapid and cost-effective method of screening for this disorder. Until then, the time-tested clinical and biochemical evaluation, including measurement of ceruloplasmin oxidase activity, slit-lamp examination for Kayser-Fleischer rings, and measurement of hepatic copper content, will continue to remain the standard for establishing the diagnosis of WD.

Adenosine Triphosphatases↗