Bruce Bacon - Academia.edu (original) (raw)

Papers by Bruce Bacon

New England Journal of Medicine, 2009

Background Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-... more Background Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. Methods At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 μg per kilogram of body weight per week or a low dose of 1.0 μg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 μg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. Results Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P = 0.20 for standarddose vs. low-dose peginterferon alfa-2b; P = 0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], −2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and −1.1% (95% CI, −5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for lowdose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. Conclusions In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferonribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials. gov number, NCT00081770.

Hepatology, 2008

One hundred and fifty patients with sustained virologic response (SVR) after treatment of chronic... more One hundred and fifty patients with sustained virologic response (SVR) after treatment of chronic hepatitis C were enrolled in a long-term clinical follow-up study; patients were followed for 5 years for liver-related outcomes and evidence of biochemical or virologic relapse. Patients with stage two or greater fibrosis on pre-treatment biopsy were invited to undergo a long-term followup biopsy after their 4 th year of follow-up. One hundred twenty-eight patients (85%) were followed through their 4 th year and long-term follow-up biopsies were obtained from 60 patients (40%). Forty-nine patients had paired pre-treatment and long-term follow-up biopsies blindly rescored. Forty of these (82%) had a decrease in fibrosis score and forty-five (92%) had a decrease in combined inflammation score. Ten patients (20%) had normal or nearly normal livers on longterm follow-up biopsy. Two patients with pre-treatment cirrhosis developed hepatocellular carcinoma (HCC) and one died. All the other patients with pre-treatment cirrhosis or advanced fibrosis had improved fibrosis scores on long-term follow-up biopsy. No patient had conclusive evidence of virologic relapse. Three patients had persistently elevated alanine aminotransferase (ALT) levels; two of these had new liver disease. In conclusion, in this cohort of 150 patients with SVR followed for five years the majority of patients had good outcomes. Serum virologic relapse was not seen but two patients with pretreatment cirrhosis developed HCC and one died. In blind rescoring of forty-nine paired pretreatment and long-term follow-up biopsies 82% improved fibrosis scores and 92% improved at least one component of inflammation. A minority of patients had normal or nearly normal liver

Annals of Internal Medicine, 2004

Postgraduate medicine, 1994

Preview Hereditary hemochromatosis, once believed to be rare, is now known to affect 1 in 250 to ... more Preview Hereditary hemochromatosis, once believed to be rare, is now known to affect 1 in 250 to 300 people of northern European descent. Untreated, the disorder can have serious complications, but for patients in whom it is discovered and treated early, the prognosis is good. In this guide to diagnosis and management, Drs Olynyk and Bacon discuss, among other things, which patients to screen, what tests to order, length of treatment, effect of treatment on complications, and prognosis.

The American journal of managed care, 2007

Chronic hepatitis C virus (HCV) infection is an area of medical and economic concern. Studies sho... more Chronic hepatitis C virus (HCV) infection is an area of medical and economic concern. Studies show a substantial and increasing use of healthcare resources by patients with this disease. However, analysis of available data regarding virologic efficacy, impact on outcomes, and cost-effectiveness in chronic HCV infection appear to justify the initial costs for antiviral treatment, considering the future cost savings generated by prevention of liver disease. To further demonstrate cost-effectiveness, enhanced methods for identifying and treating patients are needed. Greater clinician awareness of available guidelines, patient education, close monitoring of antiviral therapy, emphasis on adherence to therapy, and management of adverse effects are recommended to ensure the best possible care for patients and to maximize outcomes.

The American journal of managed care, 2007

The primary measurable goal of hepatitis C virus (HCV) therapy is permanent eradication of the vi... more The primary measurable goal of hepatitis C virus (HCV) therapy is permanent eradication of the virus (ie, a sustained virologic response [SVR]). Treatment decisions depend on the severity and treat ability of the infection, contraindications to treatment, and patient preferences. The current standard of treatment is combination therapy with pegylated interferon (peginterferon) and ribavirin. Dosages and treatment duration vary according to viral genotype. About 70% to 80% of patients with genotype 2 or 3 will achieve SVR compared with only 40% to 50% of patients with genotype 1. Generally, those who previously failed HCV treatment with monotherapy or standard interferon plus ribavirin should be considered for re-treatment with a trial of peginterferon and ribavirin. Side effects associated with treatment include influenzalike symptoms, insomnia, neutropenia, and hemolytic anemia and should be managed aggressively to promote patient adherence to therapy. Future pharmacologic agents a...

The American journal of managed care, 2005

There are at least 2.7 million individuals in the United States, most of them in their 40s and 50... more There are at least 2.7 million individuals in the United States, most of them in their 40s and 50s, who are chronically infected with hepatitis C virus (HCV). As these infected individuals get older, about 20% will develop cirrhosis, and a significant fraction of those with cirrhosis (about 1 in 10) will then develop serious decompensated liver disease or hepatocellular carcinoma. Currently, HCV is the primary cause of death in 8000 to 12 000 people every year; the virus is also the primary reason for liver transplantation in the United States. Although the number of new cases of HCV infection has been dropping steadily since the introduction of improved blood-supply screening, the "age wave" of existing chronic HCV in baby boomers is expected to contribute to a substantial rise in morbidity, mortality, and costs over the next 2 decades. Although it is difficult to predict which HCV-infected patients will progress to serious liver disease, the availability of a combination...

Seminars in Liver Disease, 2005

Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis chara... more Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. The most common form of this disorder is HFE-related HH, nearly always caused by homozygosity for the C282Y mutation. A substantial proportion of C282Y homozygotes do not develop clinically significant iron overload, suggesting roles for environmental factors and modifier genes in determining the phenotype. Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE.

Missouri medicine

Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism affecting about... more Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism affecting about 1 in 250 individuals. HH results in an increased absorption of iron at the baso-lateral surface of the enterocyte with aberrant regulation of ferroportin-mediated transfer of iron in turn brought on by a decrease in circulating hepcidin. The medical literature describes a colorful history of HH with important contributions from faculty at Saint Louis University.

Proceedings of the National Academy of Sciences, 1997

Hereditary hemochromatosis (HH) is a common autosomal recessive disease associated with loss of r... more Hereditary hemochromatosis (HH) is a common autosomal recessive disease associated with loss of regulation of dietary iron absorption and excessive iron deposition in major organs of the body. Recently, a candidate gene for HH (also called HFE) was identified that encodes a novel MHC class I-like protein. Most patients with HH are homozygous for the same mutation in the HFE gene, resulting in a C282Y change in the HFE protein. Studies in cultured cells show that the C282Y mutation abrogates the binding of the recombinant HFE protein to β 2 -microglobulin (β 2 M) and disrupts its transport to the cell surface. The HFE protein was shown by immunohistochemistry to be expressed in certain epithelial cells throughout the human alimentary tract and to have a unique localization in the cryptal cells of small intestine, where signals to regulate iron absorption are received from the body. In the studies presented here, we demonstrate by immunohistochemistry that the HFE protein is expressed...

Proceedings of the National Academy of Sciences, 1997

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism that ... more Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism that leads to excessive iron storage in the liver and other organs. Recently, between 83 and 100% of HH patients have been found to be homozygous for the same mutation in a novel major histocompatibility complex class I-like gene, called the HLA-H gene. The Cys-282 → Tyr mutation in HH patients would be expected to disrupt the function of the HLA-H gene product by altering a critical disulfide bridge. As a first step in understanding the function of the HLA-H gene product, we generated an antibody to a C-terminal peptide and used it for immunolocalization of the HLA-H protein in the gastrointestinal tract of Finnish and American subjects presumed not to have HH. Although staining for the HLA-H protein was seen in some epithelial cells in every segment of the alimentary canal, its cellular and subcellular expression in the small intestine were quite distinct from those seen in other segments. ...

Proceedings of the National Academy of Sciences, 2000

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by excess ... more Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. Liver disease resulting from iron toxicity is the major cause of death in HH. Hepatic iron loading in HH is progressive despite down-regulation of the classical transferrin receptor (TfR). Recently a human cDNA highly homologous to TfR was identified and reported to encode a protein (TfR2) that binds holotransferrin and mediates uptake of transferrin-bound iron. We independently identified a full-length murine EST encoding the mouse orthologue of the human TfR2. Although homologous to murine TfR in the coding region, the TfR2 transcript does not contain the iron-responsive elements found in the 3′ untranslated sequence of TfR mRNA. To determine the potential role for TfR2 in iron uptake by liver, we investigated TfR and TfR2 expression in normal mice and murine models of dietary iron overlo...

Proceedings of the National Academy of Sciences, 2001

Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is syst... more Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is systemic iron overload. Homozygosity for a mutation in the MHC class I heavy chain paralogue gene HFE has been found to be a primary cause of HH. However, many individuals homozygous for the defective allele of HFE do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the HH phenotype. Mice deficient in the product of the β 2 -microglobulin (β 2 M) class I light chain fail to express HFE and other MHC class I family proteins, and they have been found to manifest many characteristics of the HH phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, we performed classical genetic analysis of the iron-loading phenotype in β 2 M-deficient mice in the context of different genetic backgrounds. Strain background was found to be a major determinant in iron loading. Sex played a role that was less than...

PLoS ONE, 2009

Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum.... more Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH) is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in murine liver and duodenum. Illumina TM arrays containing over 47,000 probes were used to study global transcriptional changes. Quantitative RT-PCR (Q-RT-PCR) was used to validate the microarray results. In the liver, the expression of 151 genes was altered in Hfe 2/2 mice while dietary iron overload changed the expression of 218 genes. There were 173 and 108 differentially expressed genes in the duodenum of Hfe 2/2 mice and mice with dietary iron overload, respectively. There was 93.5% concordance between the results obtained by microarray analysis and Q-RT-PCR. Overexpression of genes for acute phase reactants in the liver and a strong induction of digestive enzyme genes in the duodenum were characteristic of the Hfe-deficient genotype. In contrast, dietary iron overload caused a more pronounced change of gene expression responsive to oxidative stress. In conclusion, Hfe deficiency caused a previously unrecognized increase in gene expression of hepatic acute phase proteins and duodenal digestive enzymes.

New England Journal of Medicine, 2005

BMC Neuroscience, 2009

Background Defective iron homeostasis may be involved in the development of some diseases within ... more Background Defective iron homeostasis may be involved in the development of some diseases within the central nervous system. Although the expression of genes involved in normal iron balance has been intensively studied in other tissues, little is known about their expression in the brain. We investigated the mRNA levels of hepcidin (HAMP), HFE, neogenin (NEO1), transferrin receptor 1 (TFRC), transferrin receptor 2 (TFR2), and hemojuvelin (HFE2) in normal human brain, brain tumors, and astrocytoma cell lines. The specimens included 5 normal brain tissue samples, 4 meningiomas, one medulloblastoma, 3 oligodendrocytic gliomas, 2 oligoastrocytic gliomas, 8 astrocytic gliomas, and 3 astrocytoma cell lines. Results Except for hemojuvelin, all genes studied had detectable levels of mRNA. In most tumor types, the pattern of gene expression was diverse. Notable findings include high expression of transferrin receptor 1 in the hippocampus and medulla oblongata compared to other brain regions,...

Journal of Clinical Investigation, 1983

J. Clin. Invest. The American Society for Clinical Investij tions of rat liver provide direct evi... more J. Clin. Invest. The American Society for Clinical Investij tions of rat liver provide direct evidence of iron-induced hepatic mitochondrial and microsomal lipid peroxidation in vivo in two models of experimental chronic iron overload. ' Abbreviations used in this paper: FeNTA, ferric nitrilotriacetate; HSF, horse spleen ferritin; MDA, malonic dialdehyde; NTA, disodium nitrilotriacetate.

New England Journal of Medicine, 2009

Background Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-... more Background Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus (HCV) infection. However, these regimens have not been adequately compared. Methods At 118 sites, patients who had HCV genotype 1 infection and who had not previously been treated were randomly assigned to undergo 48 weeks of treatment with one of three regimens: peginterferon alfa-2b at a standard dose of 1.5 μg per kilogram of body weight per week or a low dose of 1.0 μg per kilogram per week, plus ribavirin at a dose of 800 to 1400 mg per day, or peginterferon alfa-2a at a dose of 180 μg per week plus ribavirin at a dose of 1000 to 1200 mg per day. We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the standard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen. Results Among 3070 patients, rates of sustained virologic response were similar among the regimens: 39.8% with standard-dose peginterferon alfa-2b, 38.0% with low-dose peginterferon alfa-2b, and 40.9% with peginterferon alfa-2a (P = 0.20 for standarddose vs. low-dose peginterferon alfa-2b; P = 0.57 for standard-dose peginterferon alfa-2b vs. peginterferon alfa-2a). Estimated differences in response rates were 1.8% (95% confidence interval [CI], −2.3 to 6.0) between standard-dose and low-dose peginterferon alfa-2b and −1.1% (95% CI, −5.3 to 3.0) between standard-dose peginterferon alfa-2b and peginterferon alfa-2a. Relapse rates were 23.5% (95% CI, 19.9 to 27.2) for standard-dose peginterferon alfa-2b, 20.0% (95% CI, 16.4 to 23.6) for lowdose peginterferon alfa-2b, and 31.5% (95% CI, 27.9 to 35.2) for peginterferon alfa-2a. The safety profile was similar among the three groups; serious adverse events were observed in 8.6 to 11.7% of patients. Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12, a sustained virologic response was achieved in 86.2% and 78.7%, respectively. Conclusions In patients infected with HCV genotype 1, the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferonribavirin regimens or between the two doses of peginterferon alfa-2b. (ClinicalTrials. gov number, NCT00081770.

Hepatology, 2008

One hundred and fifty patients with sustained virologic response (SVR) after treatment of chronic... more One hundred and fifty patients with sustained virologic response (SVR) after treatment of chronic hepatitis C were enrolled in a long-term clinical follow-up study; patients were followed for 5 years for liver-related outcomes and evidence of biochemical or virologic relapse. Patients with stage two or greater fibrosis on pre-treatment biopsy were invited to undergo a long-term followup biopsy after their 4 th year of follow-up. One hundred twenty-eight patients (85%) were followed through their 4 th year and long-term follow-up biopsies were obtained from 60 patients (40%). Forty-nine patients had paired pre-treatment and long-term follow-up biopsies blindly rescored. Forty of these (82%) had a decrease in fibrosis score and forty-five (92%) had a decrease in combined inflammation score. Ten patients (20%) had normal or nearly normal livers on longterm follow-up biopsy. Two patients with pre-treatment cirrhosis developed hepatocellular carcinoma (HCC) and one died. All the other patients with pre-treatment cirrhosis or advanced fibrosis had improved fibrosis scores on long-term follow-up biopsy. No patient had conclusive evidence of virologic relapse. Three patients had persistently elevated alanine aminotransferase (ALT) levels; two of these had new liver disease. In conclusion, in this cohort of 150 patients with SVR followed for five years the majority of patients had good outcomes. Serum virologic relapse was not seen but two patients with pretreatment cirrhosis developed HCC and one died. In blind rescoring of forty-nine paired pretreatment and long-term follow-up biopsies 82% improved fibrosis scores and 92% improved at least one component of inflammation. A minority of patients had normal or nearly normal liver

Annals of Internal Medicine, 2004

Postgraduate medicine, 1994

Preview Hereditary hemochromatosis, once believed to be rare, is now known to affect 1 in 250 to ... more Preview Hereditary hemochromatosis, once believed to be rare, is now known to affect 1 in 250 to 300 people of northern European descent. Untreated, the disorder can have serious complications, but for patients in whom it is discovered and treated early, the prognosis is good. In this guide to diagnosis and management, Drs Olynyk and Bacon discuss, among other things, which patients to screen, what tests to order, length of treatment, effect of treatment on complications, and prognosis.

The American journal of managed care, 2007

Chronic hepatitis C virus (HCV) infection is an area of medical and economic concern. Studies sho... more Chronic hepatitis C virus (HCV) infection is an area of medical and economic concern. Studies show a substantial and increasing use of healthcare resources by patients with this disease. However, analysis of available data regarding virologic efficacy, impact on outcomes, and cost-effectiveness in chronic HCV infection appear to justify the initial costs for antiviral treatment, considering the future cost savings generated by prevention of liver disease. To further demonstrate cost-effectiveness, enhanced methods for identifying and treating patients are needed. Greater clinician awareness of available guidelines, patient education, close monitoring of antiviral therapy, emphasis on adherence to therapy, and management of adverse effects are recommended to ensure the best possible care for patients and to maximize outcomes.

The American journal of managed care, 2007

The primary measurable goal of hepatitis C virus (HCV) therapy is permanent eradication of the vi... more The primary measurable goal of hepatitis C virus (HCV) therapy is permanent eradication of the virus (ie, a sustained virologic response [SVR]). Treatment decisions depend on the severity and treat ability of the infection, contraindications to treatment, and patient preferences. The current standard of treatment is combination therapy with pegylated interferon (peginterferon) and ribavirin. Dosages and treatment duration vary according to viral genotype. About 70% to 80% of patients with genotype 2 or 3 will achieve SVR compared with only 40% to 50% of patients with genotype 1. Generally, those who previously failed HCV treatment with monotherapy or standard interferon plus ribavirin should be considered for re-treatment with a trial of peginterferon and ribavirin. Side effects associated with treatment include influenzalike symptoms, insomnia, neutropenia, and hemolytic anemia and should be managed aggressively to promote patient adherence to therapy. Future pharmacologic agents a...

The American journal of managed care, 2005

There are at least 2.7 million individuals in the United States, most of them in their 40s and 50... more There are at least 2.7 million individuals in the United States, most of them in their 40s and 50s, who are chronically infected with hepatitis C virus (HCV). As these infected individuals get older, about 20% will develop cirrhosis, and a significant fraction of those with cirrhosis (about 1 in 10) will then develop serious decompensated liver disease or hepatocellular carcinoma. Currently, HCV is the primary cause of death in 8000 to 12 000 people every year; the virus is also the primary reason for liver transplantation in the United States. Although the number of new cases of HCV infection has been dropping steadily since the introduction of improved blood-supply screening, the "age wave" of existing chronic HCV in baby boomers is expected to contribute to a substantial rise in morbidity, mortality, and costs over the next 2 decades. Although it is difficult to predict which HCV-infected patients will progress to serious liver disease, the availability of a combination...

Seminars in Liver Disease, 2005

Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis chara... more Hereditary hemochromatosis (HH) encompasses several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorption and tissue iron deposition. The most common form of this disorder is HFE-related HH, nearly always caused by homozygosity for the C282Y mutation. A substantial proportion of C282Y homozygotes do not develop clinically significant iron overload, suggesting roles for environmental factors and modifier genes in determining the phenotype. Recent studies have demonstrated that the pathogenesis of nearly all forms of HH involves inappropriately decreased expression of the iron-regulatory hormone hepcidin. Hepcidin serves to decrease the export of iron from reticuloendothelial cells and absorptive enterocytes. Thus, HH patients demonstrate increased iron release from these cell types, elevated circulating iron, and iron deposition in vulnerable tissues. The mechanism by which HFE influences hepcidin expression is an area of current investigation and may offer insights into the phenotypic variability observed in persons with mutations in HFE.

Missouri medicine

Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism affecting about... more Hereditary hemochromatosis (HH) is a common inherited disorder of iron metabolism affecting about 1 in 250 individuals. HH results in an increased absorption of iron at the baso-lateral surface of the enterocyte with aberrant regulation of ferroportin-mediated transfer of iron in turn brought on by a decrease in circulating hepcidin. The medical literature describes a colorful history of HH with important contributions from faculty at Saint Louis University.

Proceedings of the National Academy of Sciences, 1997

Hereditary hemochromatosis (HH) is a common autosomal recessive disease associated with loss of r... more Hereditary hemochromatosis (HH) is a common autosomal recessive disease associated with loss of regulation of dietary iron absorption and excessive iron deposition in major organs of the body. Recently, a candidate gene for HH (also called HFE) was identified that encodes a novel MHC class I-like protein. Most patients with HH are homozygous for the same mutation in the HFE gene, resulting in a C282Y change in the HFE protein. Studies in cultured cells show that the C282Y mutation abrogates the binding of the recombinant HFE protein to β 2 -microglobulin (β 2 M) and disrupts its transport to the cell surface. The HFE protein was shown by immunohistochemistry to be expressed in certain epithelial cells throughout the human alimentary tract and to have a unique localization in the cryptal cells of small intestine, where signals to regulate iron absorption are received from the body. In the studies presented here, we demonstrate by immunohistochemistry that the HFE protein is expressed...

Proceedings of the National Academy of Sciences, 1997

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism that ... more Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism that leads to excessive iron storage in the liver and other organs. Recently, between 83 and 100% of HH patients have been found to be homozygous for the same mutation in a novel major histocompatibility complex class I-like gene, called the HLA-H gene. The Cys-282 → Tyr mutation in HH patients would be expected to disrupt the function of the HLA-H gene product by altering a critical disulfide bridge. As a first step in understanding the function of the HLA-H gene product, we generated an antibody to a C-terminal peptide and used it for immunolocalization of the HLA-H protein in the gastrointestinal tract of Finnish and American subjects presumed not to have HH. Although staining for the HLA-H protein was seen in some epithelial cells in every segment of the alimentary canal, its cellular and subcellular expression in the small intestine were quite distinct from those seen in other segments. ...

Proceedings of the National Academy of Sciences, 2000

Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by excess ... more Hereditary hemochromatosis (HH) is a common autosomal recessive disorder characterized by excess absorption of dietary iron and progressive iron deposition in several tissues, particularly liver. Liver disease resulting from iron toxicity is the major cause of death in HH. Hepatic iron loading in HH is progressive despite down-regulation of the classical transferrin receptor (TfR). Recently a human cDNA highly homologous to TfR was identified and reported to encode a protein (TfR2) that binds holotransferrin and mediates uptake of transferrin-bound iron. We independently identified a full-length murine EST encoding the mouse orthologue of the human TfR2. Although homologous to murine TfR in the coding region, the TfR2 transcript does not contain the iron-responsive elements found in the 3′ untranslated sequence of TfR mRNA. To determine the potential role for TfR2 in iron uptake by liver, we investigated TfR and TfR2 expression in normal mice and murine models of dietary iron overlo...

Proceedings of the National Academy of Sciences, 2001

Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is syst... more Hereditary hemochromatosis (HH) is a common chronic human genetic disorder whose hallmark is systemic iron overload. Homozygosity for a mutation in the MHC class I heavy chain paralogue gene HFE has been found to be a primary cause of HH. However, many individuals homozygous for the defective allele of HFE do not develop iron overload, raising the possibility that genetic variation in modifier loci contributes to the HH phenotype. Mice deficient in the product of the β 2 -microglobulin (β 2 M) class I light chain fail to express HFE and other MHC class I family proteins, and they have been found to manifest many characteristics of the HH phenotype. To determine whether natural genetic variation plays a role in controlling iron overload, we performed classical genetic analysis of the iron-loading phenotype in β 2 M-deficient mice in the context of different genetic backgrounds. Strain background was found to be a major determinant in iron loading. Sex played a role that was less than...

PLoS ONE, 2009

Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum.... more Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH) is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in murine liver and duodenum. Illumina TM arrays containing over 47,000 probes were used to study global transcriptional changes. Quantitative RT-PCR (Q-RT-PCR) was used to validate the microarray results. In the liver, the expression of 151 genes was altered in Hfe 2/2 mice while dietary iron overload changed the expression of 218 genes. There were 173 and 108 differentially expressed genes in the duodenum of Hfe 2/2 mice and mice with dietary iron overload, respectively. There was 93.5% concordance between the results obtained by microarray analysis and Q-RT-PCR. Overexpression of genes for acute phase reactants in the liver and a strong induction of digestive enzyme genes in the duodenum were characteristic of the Hfe-deficient genotype. In contrast, dietary iron overload caused a more pronounced change of gene expression responsive to oxidative stress. In conclusion, Hfe deficiency caused a previously unrecognized increase in gene expression of hepatic acute phase proteins and duodenal digestive enzymes.

New England Journal of Medicine, 2005

BMC Neuroscience, 2009

Background Defective iron homeostasis may be involved in the development of some diseases within ... more Background Defective iron homeostasis may be involved in the development of some diseases within the central nervous system. Although the expression of genes involved in normal iron balance has been intensively studied in other tissues, little is known about their expression in the brain. We investigated the mRNA levels of hepcidin (HAMP), HFE, neogenin (NEO1), transferrin receptor 1 (TFRC), transferrin receptor 2 (TFR2), and hemojuvelin (HFE2) in normal human brain, brain tumors, and astrocytoma cell lines. The specimens included 5 normal brain tissue samples, 4 meningiomas, one medulloblastoma, 3 oligodendrocytic gliomas, 2 oligoastrocytic gliomas, 8 astrocytic gliomas, and 3 astrocytoma cell lines. Results Except for hemojuvelin, all genes studied had detectable levels of mRNA. In most tumor types, the pattern of gene expression was diverse. Notable findings include high expression of transferrin receptor 1 in the hippocampus and medulla oblongata compared to other brain regions,...

Journal of Clinical Investigation, 1983

J. Clin. Invest. The American Society for Clinical Investij tions of rat liver provide direct evi... more J. Clin. Invest. The American Society for Clinical Investij tions of rat liver provide direct evidence of iron-induced hepatic mitochondrial and microsomal lipid peroxidation in vivo in two models of experimental chronic iron overload. ' Abbreviations used in this paper: FeNTA, ferric nitrilotriacetate; HSF, horse spleen ferritin; MDA, malonic dialdehyde; NTA, disodium nitrilotriacetate.