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Bruce R Bacon

Publications and source records attributed to Bruce R Bacon.

At least 37 records · Page 2Linked to original sources
PubMed2005

Chronic hepatitis C: an age wave of disease burden.

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 drug regimen (peginterferon alfa plus ribavirin) that essentially "cures" the disease in more than half of treated patients now provides clinicians and pharmacists in managed care settings with the tools needed to diminish the impact of the anticipated wave of liver disease. This article reviews the epidemiology, natural history, clinical and economic burden, and screening and treatment options for HCV.

Antiviral Agents↗
PubMed2005

Treatment issues with chronic hepatitis C: special populations and pharmacy strategies.

Combination therapy with peginterferon alfa and ribavirin now eliminates detectable hepatitis C virus (HCV) from the blood of more than half of patients with long-term infections. However, many of those infected with HCV have low rates of response to therapy and/or are more susceptible to drug side effects that limit adherence to therapy. African Americans with HCV, for example, tend to be more difficult to cure with drug therapy. Individuals coinfected with both human immunodeficiency virus and HCV are also more difficult to treat. As managed care organizations begin offering anti-HCV therapy to a broader range of patients, special strategies for limiting medication side effects and enhancing overall clinical and economic outcomes will become more important. In particular, assessing the early virologic response to therapy at 12 weeks can help clinicians identify patients who are highly likely to be responsive at the end of the full course, while also identifying likely nonresponders--who can be taken off therapy and thereby avoid unnecessary side effects and costs. In all patients remaining on therapy, efforts to boost adherence will also enhance the overall rate of sustained virologic response. Special attention should be paid to managing depression and cytopenias with patient education and either dose reduction or use of hematopoietic growth factors. These 2 basic treatment strategies--of stopping treatment early or, alternatively, of pressing for full patient compliance over the full course of therapy--are flip sides of the same management coin that health plans and clinicians can employ to optimize results and cost effectiveness with the current standard of therapy for chronic HCV infection.

Antiviral Agents↗
PubMed2004

Testing for hepatitis C virus infection should be routine for persons at increased risk for infection.

In the United States, chronic hepatitis C virus (HCV) infection affects an estimated 3 million persons, most younger than 50 years of age. It is one of the leading causes of chronic liver disease morbidity and mortality and the most common indication for liver transplantation. Effective treatment can eradicate the virus and eliminate or reduce liver inflammation and fibrosis, and counseling and immunization can modify or prevent the adverse effect of cofactors (for example, alcohol consumption or co-infections) on disease progression. However, controversy surrounds the need to routinely identify asymptomatic HCV-infected persons. Because no data currently demonstrate that treatment or other interventions will reduce future cases of HCV-related chronic disease and deaths, the U.S. Preventive Services Task Force found insufficient evidence to recommend for or against routine screening for HCV infection in adults at high risk. Chronic hepatitis C would require many years of follow-up to determine the incidence of complication after treatment of or other interventions in asymptomatic persons. It seems inappropriate to wait several decades to measure the impact of early identification of this viral infection when current data support a positive therapeutic effect that points to long-term benefits. In addition, treatment and other interventions must be provided before cirrhosis or liver failure occurs. Therefore, medical and public health professionals should continue the practice of screening persons for risk factors; offering testing to those at increased risk for HCV infection; and providing infected persons with appropriate counseling, medical evaluation, and treatment.

Hepacivirus↗
PubMed2004

Pathogenesis of hereditary hemochromatosis.

Hereditary hemochromatosis comprises several inherited disorders of iron homeostasis characterized by increased gastrointestinal iron absorpstion and resultant tissue iron deposition. The identification of HFE and other genes involved in iron metabolism has greatly expanded our understanding of hereditary hemochromatosis. Two major hypotheses have been proposed to explain the pathogenesis of HFE-related hereditary hemochromatosis: the hepcidin hypothesis and the duodenal crypt cell programming hypothesis.

Animals↗
PubMed2004

Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens.

Thirty overweight patients with clinically characterized and biopsy proven nonalcoholic steatohepatitis (NASH) were enrolled in a 48-week treatment trial with rosiglitazone, a peroxisome proliferator-activator receptor (PPAR)-gamma agonist that enhances insulin sensitivity. Improvement in laboratory liver tests, insulin resistance and liver fat content were documented; blinded biopsy review demonstrated decreases in necroinflammatory activity or grade and in individual components of grade, and changes in the relationship of lobular and portal inflammation as well as in the nature of perisinusoidal fibrosis. The current study identified correlations of histological features of the protocol entry biopsy specimens with contemporaneous laboratory and imaging tests. Significant correlations with histologically assessed steatosis were liver fat, evaluated by computed tomography (P = 0.001); mean HbA1C, a measure of glycemic control (P = 0.004); and QUICKI, a measure of insulin sensitivity (P = 0.05). Histologically determined grades of steatohepatitis (SH) correlated with HbA1C (P = 0.01), and a trend toward elevated fasting glucose levels was seen. No subject in the study was cirrhotic at entry; fibrosis scores of the 30 subjects did not significantly correlate with age, gender, body mass index, or clinical tests. All subjects underwent 3 biopsies (prior, entry, and posttreatment), and all had undergone a prior biopsy with diagnostic SH. By blinded analysis, 7 study entry biopsy specimens did not fulfill published strict criteria for SH. Laboratory results from these subjects included normal fasting glucose level and, compared with the 23 subjects with criteria for SH, lower mean alanine aminotransferase and aspartate aminotransferase levels (P = 0.02 for both), less insulin resistance (P = 0.03), and lower mean HbA1C (P = 0.001). We conclude that biopsy findings determined by blinded analysis correlated with image-detected steatosis, laboratory markers of hepatic inflammation, insulin resistance, and long-term glycemia; the findings confirm the usefulness of strict histological criteria in the evaluation of NASH.

Biopsy↗
PubMed2004

Infection with hepatitis C virus genotype 4 in the United States.

BACKGROUND: Hepatitis C virus genotype differences seem to be of considerable clinical significance because they affect responses to antiviral therapy. HCV genotype 4 is rare in the United States and there are few published data regarding response to therapy in patients with HCV genotype 4 infection. OBJECTIVES: To assess epidemiologic factors associated with HCV genotype 4 infection in United States and to describe the response rate to therapy with the combination of alpha interferon and ribavirin. METHODS: All hepatologists in our Division were asked for information about patients they had treated with HCV genotype 4. In addition, we searched the computer database from Saint Louis University Hospital in the last 40 months (1999 to 2002). Twenty HCV genotype 4 patients were identified. A retrospective chart review was performed to collect information about their demographics, risk factors for acquisition of infection, baseline laboratory studies and response to antiviral therapy. RESULTS: A risk factor for exposure to HCV was noted in 14 cases (70%); 12 patients had a history of illicit drug use, whereas a history of blood transfusion was detected in three cases; 1 patient had both risk factors. Only 4 of 20 individuals had fibrosis stage 3 or 4 on liver biopsy. Seventeen patients were treated, 14 of whom completed therapy; 10 patients were sustained responders. CONCLUSIONS: As with other HCV genotypes, most patients with HCV genotype 4 in the United States acquire the infection through intravenous drug use, liver disease is often mild to moderate in severity and 59% of our patients had a sustained virologic response after combination therapy with interferon and ribavirin.

Adult↗
PubMed2004

CD14-positive hepatic monocytes/macrophages increase in hereditary hemochromatosis.

BACKGROUND/AIMS: Iron overload in hereditary hemochromatosis (HH) may result in hepatic fibrosis and cirrhosis, primarily due to collagen production by hepatic stellate cells that become activated to myofibroblasts. Endotoxin-responsive monocytes/macrophages (CD14-positive) are potential sources of profibrogenic factors. The aims of this study were to determine (1) whether CD14-positive monocytes/macrophages are present in the livers of patients with HH and (2) the potential relationship between CD14-positive cells and hepatic fibrosis in HH. METHODS: HH was diagnosed using standard clinical, biochemical and genotypic parameters. Liver specimens from HH patients and control subjects were immunostained for CD14, CD68 and alpha-smooth muscle actin (alpha-SMA) and the number of cells expressing these antigens was determined. Fibrosis was assessed by routine histological methods. RESULTS: The total number of hepatic CD68-positive monocytes/macrophages was similar in HH patients and control subjects; however, there was a nine-fold increase in the number of CD14-positive monocytes/macrophages in HH patients. Control subjects had very low levels of hepatic CD14 expression. In HH livers with advanced fibrosis, CD14-positive monocytes/macrophages were often associated with fibrous septa containing myofibroblasts expressing alpha-SMA. CONCLUSIONS: There was a substantial increase in hepatic CD14-positive monocytes/macrophages in HH and, in livers with advanced fibrosis, these cells were often associated with fibrous septa and septal myofibroblasts. The total number of monocytes/macrophages was similar in HH and control livers. In control human liver, Kupffer cells had a very low expression of CD14. These findings suggest that CD14-positive monocytes/macrophages may contribute to the process of hepatic fibrogenesis in HH.

Adult↗
PubMed2004

Disease- and cell-specific expression of GP73 in human liver disease.

OBJECTIVES: GP73, a Golgi membrane protein, is expressed at high levels in hepatocytes of patients with decompensated cirrhosis. Its expression in other forms of liver disease has not been investigated. Therefore, we studied GP73 expression in patients with noncirrhotic liver disease. METHODS: GP73 expression was detected immunohistochemically and by immunofluorescence microscopy in patients with acute hepatitis of various etiologies, autoimmune hepatitis, chronic HCV infection, and alcoholic liver disease. In order to quantitate hepatocyte GP73 expression, an immunohistochemical scoring system was developed, and validated by a direct comparison with GP73 protein levels as determined by Western blotting. RESULTS: GP73 immunostaining and Western blotting data were highly correlated, demonstrating the suitability of the immunohistochemical scoring system to quantitate hepatocyte GP73 expression. Hepatocyte GP73 expression was increased in patients with acute and autoimmune hepatitis. Treatment of autoimmune hepatitis was associated with a normalization of GP73 expression, indicating that the initial upregulation was reversible. Increased levels of GP73 expression were also noted in chronic HCV infection and alcoholic liver disease. Under these conditions, GP73 levels were correlated with disease stage but not grade. GP73 immunoreactivity was occasionally detected in alpha-SMA-positive, sinusoidal lining cells, suggesting activated stellate cells as a potential source of GP73. CONCLUSIONS: Hepatocyte GP73 levels are upregulated in acute hepatitis and during the progression of liver disease to cirrhosis. This expression pattern suggests the presence of two regulatory mechanisms, the first triggered during acute hepatocellular injury, the second during the progression of chronic liver disease.

Acute Disease↗
PubMed2004

Chronic hepatitis C and normal ALT: considerations for treatment.

Improvements in the treatment of patients with chronic hepatitis C have progressed over the past 14 yr. Initially, treatment of patients with persistently normal ALT levels was not considered necessary. As treatment response improved, more of these patients were treated. Jacobson and colleagues have shown that patients with normal ALT levels respond similarly to those with elevated ALT levels when treated with the combination of interferon and ribavirin. ALT levels are a poor marker of disease severity and/or indication for treatment in patients with chronic hepatitis C.

Adult↗
PubMed2004

Managing hepatitis C.

Availability of a drug regimen that eradicates the hepatitis C virus (HCV) in more than half of treated patients provides the medical community with a powerful new weapon to diminish the anticipated future wave of HCV-related liver disease and cancer. Clinicians must understand the benefits, risks, and costs associated with the combination of peginterferon alfa and ribavirin. Major clinical trials with this new standard of HCV therapy have demonstrated sustained virologic responses of 54% and 56% with 48 weeks of combination therapy. Response is highest in those with genotype 2/3, with early virologic response by week 12, in patients with high adherence, and in patients receiving weight-appropriate ribavirin dosages. The most common side effects are manageable and include fatigue, headache, myalgia, rigors, fever, nausea, insomnia, and depression. Neutropenia associated with interferon and anemia associated with ribavirin are more serious side effects that can cause discontinuation or dose reduction. Clinicians can maximize results and reduce costs with a regimen of peginterferon alfa plus ribavirin by choosing patients carefully, educating patients thoroughly, stopping therapy early in those patients who do not respond by week 12 of therapy, and enhancing adherence by managing side effects with appropriate dose reductions and/or selective use of antidepressants or hematopoietic colony stimulators.

Antiviral Agents↗
PubMed2004

Evaluation of serum anion gap in patients with liver cirrhosis of diverse etiologies.

BACKGROUND: The low serum anion gap (AG) in patients with hepatic cirrhosis is generally attributed to hypoalbuminemia. Serum immunoglobulin G (IgG) (elevated in chronic viral hepatitis) and IgA (elevated in alcoholic cirrhosis) have different isoelectric points, and thus may affect serum AG in opposite directions. AIM: To define the normal serum AG in patients with liver cirrhosis of diverse etiologies. STUDY DESIGN: We retrospectively compared serum AG of 144 stable cirrhotics and 286 control patients (consecutive hospital admissions with serum creatinine concentration < 2 mg/dL). RESULTS: Serum AG was significantly lower among the cirrhotics, compared to the controls (5.8 +/- 2.2 mEq/L vs. 7.0 +/- 2.2 mEq/L, respectively, p<0.005). However, when patients with serum albumin concentration < 3.5 g/dL were excluded, there was no significant difference between the cirrhotics vs. controls (6.7 +/- 1.8 mEq/L vs. 7.0 +/- 2.2 mEq/L, p=ns). Moreover, patients with liver cirrhosis secondary to chronic viral hepatitis had AG similar to that of the alcoholic cirrhotics (5.6 +/- 2.5 mEq/L vs. 6.0 +/- 1.9 mEq/L, p=ns). There was a positive correlation between serum albumin concentrations > 1.9 g/dL and serum AG, and a tendency toward an inverse correlation between serum globulin concentration and serum AG. CONCLUSION: Our results support the contention that hypoalbuminemia accounts for the decreased serum AG frequently observed in patients with liver cirrhosis. We found no difference in serum AG with different causes of cirrhosis. We also suggest a lower reference range for normal serum AG.

Acid-Base Equilibrium↗
PubMed2003

Contribution of the H63D mutation in HFE to murine hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is an autosomal recessive disease characterized by iron accumulation in several organs, followed by organ damage and failure. The C282Y mutation in the HFE gene explains 80-90% of all diagnosed cases of HH in populations of northwestern European ancestry. Targeted disruption of the mouse Hfe gene (or introduction of the murine mutation analogous to the C282Y human mutation) produces a murine model of HH. Another mutation in the HFE gene, H63D, is more prevalent than C282Y. However, the physiological consequences of the H63D mutation (as well as C282Y/H63D compound heterozygosity) on iron homeostasis are less well established. To evaluate the phenotypic consequences of the C282Y/H63D and H63D/H63D genotypes, we produced H67D (corresponding to H63D in humans) and C294Y (corresponding to C282Y in humans) knock-in mice. H67D homozygous mice, C294Y homozygous mice, and H67D/C294Y compound heterozygous mice each demonstrated hepatic iron loading. Even on a standard diet, by 10 weeks of age, hepatic iron levels in mice of these three genotypes were significantly higher than those of wild-type littermates. The relative severity of hepatic iron loading was C294Y/C294Y > C294Y/H67D > H67D/H67D. We conclude that the H67D allele, when homozygous or combined with a more consequential mutation like C294Y, leads to hepatic iron loading. These observations indicate that the H67D mutation leads to partial loss of Hfe function and can contribute to murine HH.

Amino Acid Substitution↗
PubMed2003

The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells.

Chronic ethanol consumption can result in hepatic fibrosis and cirrhosis. In addition to oxidative metabolism, ethanol can be metabolized by esterification with fatty acids to form fatty acid ethyl esters (FAEE) such as linolenic acid ethyl ester (LAEE). We have previously demonstrated that LAEE has promitogeinc and activating effects on hepatic stellate cells (HSC), but the mechanisms of these actions are not known. Intracellular signaling through MAP kinase pathways, including extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) can influence the activity of the transcription factor AP-1, while cell-cycle regulatory proteins such as cyclin E and cyclin-dependent kinase (CDK), play an important role in cell proliferation. In this study, we demonstrate that treatment of HSC with LAEE increases cyclin E expression and cyclin E/CDK2 activity, which may underlie the promitogenic effects of this compound. In addition, LAEE increases ERK and JNK activity, and these pathways play an important role in the activation of AP-1-dependent gene expression by LAEE. The stimulation of intracellular signaling pathways in HSC by this well-characterized ethanol metabolite may contribute to ethanol-induced hepatic fibrogenesis.

Animals↗
PubMed2003

Interim results of a pilot study demonstrating the early effects of the PPAR-gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non-alcoholic steatohepatitis.

BACKGROUND/AIMS: Hyperinsulinemia may cause hepatic steatosis and non-alcoholic steatohepatitis (NASH). The aims of this pilot study were to examine the safety of using the insulin-sensitizing peroxisomal proliferator activated receptor (PPAR) gamma ligand rosiglitazone in patients with NASH and determine whether improved insulin sensitivity correlates with improved fatty liver. METHODS: Thirty subjects with NASH and elevated alanine aminotransferase (ALT) levels received rosiglitazone, 4 mg twice daily for 48 weeks; the preliminary results presented here were obtained at 24 weeks. Insulin sensitivity was measured using fasting insulin and glucose levels and liver fat content was estimated by CT imaging. RESULTS: By 24 weeks, rosiglitazone improved insulin sensitivity and reduced liver fat content. The mean ALT decreased from 86 to 37 U/l (P<0.01). Four subjects (13%) withdrew, one because of a rise in ALT from 59 to 277 U/l that coincided with concomitant prednisone use. Subjects experienced a mean weight gain of 3.5% and hemoglobin drop of 1.1 g/dl. CONCLUSIONS: Treatment of NASH with rosiglitazone for 24 weeks improved insulin sensitivity, reduced liver fat content and improved biochemical evidence of hepatocellular injury. These preliminary data provide evidence that hyperinsulinemia may be a cause of NASH. Strategies to improve insulin sensitivity as a treatment of NASH deserve further investigation.

Adult↗