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Biomedical subjects

E M Brunt

Publications and source records attributed to E M Brunt.

At least 19 recordsLinked to original sources
PubMed2001

Mouse strain differences determine severity of iron accumulation in Hfe knockout model of hereditary hemochromatosis.

Hereditary hemochromatosis (HH) is a common disorder of iron metabolism caused by mutation in HFE, a gene encoding an MHC class I-like protein. Clinical studies demonstrate that the severity of iron loading is highly variable among individuals with identical HFE genotypes. To determine whether genetic factors other than Hfe genotype influence the severity of iron loading in the murine model of HH, we bred the disrupted murine Hfe allele onto three different genetically defined mouse strains (AKR, C57BL/6, and C3H), which differ in basal iron status and sensitivity to dietary iron loading. Serum transferrin saturations (percent saturation of serum transferrin with iron), hepatic and splenic iron concentrations, and hepatocellular iron distribution patterns were compared for wild-type (Hfe +/+), heterozygote (Hfe +/-), and knockout (Hfe -/-) mice from each strain. Although the Hfe -/- mice from all three strains demonstrated increased transferrin saturations and liver iron concentrations compared with Hfe +/+ mice, strain differences in severity of iron accumulation were striking. Targeted disruption of the Hfe gene led to hepatic iron levels in Hfe -/- AKR mice that were 2.5 or 3.6 times higher than those of Hfe -/- C3H or Hfe -/- C57BL/6 mice, respectively. The Hfe -/- mice also demonstrated strain-dependent differences in transferrin saturation, with the highest values in AKR mice and the lowest values in C3H mice. These observations demonstrate that heritable factors markedly influence iron homeostasis in response to Hfe disruption. Analysis of mice from crosses between C57BL/6 and AKR mice should allow the mapping and subsequent identification of genes modifying the severity of iron loading in this murine model of HH.

Animals↗
PubMed2001

Immunohistochemical detection of myeloperoxidase and its oxidation products in Kupffer cells of human liver.

Oxidative damage to tissue proteins has been implicated in the pathogenesis of liver disease, but the mechanisms that promote oxidation in vivo are unclear. Hydrogen peroxide is transformed into an array of potentially damaging reactants by the heme protein myeloperoxidase. This proinflammatory enzyme is expressed by circulating neutrophils and monocytes but is generally thought to be absent from tissue macrophages. To determine whether myeloperoxidase is present in Kupffer cells, the fixed-tissue macrophages of liver, Western blot analysis, and immunohistochemistry were performed. Two different antibodies monospecific for myeloperoxidase identified a 60-kd protein, the predicted molecular mass of myeloperoxidase, in human liver extracts. Immunostaining detected the enzyme in sinusoidal lining cells of normal and diseased human livers. Immunofluorescence confocal microscopy demonstrated co-localization of myeloperoxidase and CD68, a monocyte/macrophage marker, in sinusoidal lining cells. Numerous myeloperoxidase-expressing cells were also evident in the fibrous septa of cirrhotic livers. Immunostaining with an antibody to proteins modified by hypochlorous acid, a characteristic product of the enzyme, indicated that myeloperoxidase is enzymatically active in cases of acute liver injury and cirrhosis. These findings identify myeloperoxidase as a component of human Kupffer cells. Oxidative damage resulting from the action of myeloperoxidase may contribute to acute liver injury and hepatic fibrogenesis.

Animals↗
PubMed2001

Benign tumors of the liver.

Benign tumors of the liver, less commonly encountered than metastatic or primary liver tumors, may present clinically with symptoms due to mass effect, or may be discovered incidentally during radiographic evaluation or surgical exploration for other clinical indications. Many of the lesions that result in a benign liver mass are true neoplasms, while others result from reactive proliferation of hepatocytes, biliary cells, mesenchymal or inflammatory cells. The premalignant nature or potential for malignant transformation is of concern in some of the benign tumors or tumor-like masses of the liver. In this article, benign tumors and tumor-like masses involving the adult liver are discussed with a focus on histopathology, histogenesis, and clinical significance of these interesting and unusual lesions.

Adenoma↗
PubMed2001

Combination of interferon and ribavirin in chronic hepatitis C: re-treatment of nonresponders to interferon.

Chronic infection with hepatitis C virus (HCV) may result in cirrhosis, liver failure, and hepatocellular carcinoma. A minority of patients have a sustained response to antiviral therapy, and nonresponders remain at risk of developing progressive liver disease. We conducted a randomized, controlled trial of therapy with the combination of interferon (IFN) and ribavirin in patients with chronic hepatitis C who had not responded to an initial course of therapy with IFN alone. A total of 124 patients were randomized to receive the combination of IFN and ribavirin for either 24 or 48 weeks and followed for an additional 24 weeks after stopping therapy. Thirty-eight treated patients (30.6%) achieved a sustained virologic response (undetectable HCV RNA at the 24-week follow-up point). This was associated with significant improvement in necroinflammatory activity noted on liver biopsy. Interestingly, there was not a statistically significant difference in response rates based on the duration of treatment; HCV genotype was the strongest predictor of a sustained response. Sustained responses were noted even in patients with poor predictive factors, including those with advanced hepatic fibrosis or cirrhosis, high levels of HCV RNA in serum, and those infected with HCV genotype 1. The study included 24 patients with normal serum alanine transaminase (ALT) values before therapy who had similar responses to those with initially elevated transaminase values. This study suggests that the combination of IFN and ribavirin is a useful modality of therapy in patients with chronic hepatitis C who did not respond to IFN alone.

Adult↗
PubMed2001

Nonalcoholic steatohepatitis: definition and pathology.

Nonalcoholic steatohepatitis (NASH) is a significant form of chronic liver disease in adults and children. The natural history of NASH ranges from indolent to end-stage liver disease. Current studies are focusing on identification of histologic and/or clinical markers of progression. NASH may be an underlying cause of cryptogenic cirrhosis, and the lesions of NASH may recur in allograft livers. An expanding array of clinical conditions and pathogenetic mechanisms have been identified, but many cases remain "idiopathic"; lack of significant alcohol use is, by definition, common to all cases. Neither clinical evaluation nor laboratory values can ensure either the diagnosis or the exclusion of NASH, and liver biopsy interpretation continues to be considered the "gold standard" for diagnosis. The lesions in NASH are similar but not identical to those of alcoholic steatohepatitis; exact, specific histologic criteria for the diagnosis are currently under discussion. The lesions most commonly accepted for NASH include steatosis, hepatocyte ballooning degeneration, mild diffuse lobular mixed acute and chronic inflammation, and perivenular, perisinusoidal collagen deposition. Zone 3 accentuation may be detected. Mallory's hyaline, vacuolated nuclei in periportal hepatocytes, lobular lipogranulomas, and PAS-diastase-resistant Kupffer cells are common. In biopsy specimens from children, portal inflammation may be more prominent than in adults. Progression of fibrosis may result in bridging septa and cirrhosis. The lesions of steatohepatitis may be noted concurrently with other forms of chronic liver disease. A histological "grading and staging" system has been developed to reflect the unique features of steatohepatitis, gradations of severity and fibrosis, and to promote uniform reporting of the histopathology.

Biopsy↗
PubMed2001

Chronology of histological changes after band ligation of esophageal varices in humans.

BACKGROUND AND STUDY AIMS: While the histological effects of endoscopic sclerotherapy in humans have been extensively described, the effects of endoscopic ligation have been reported in only two cases. The purpose of this study was to reconstruct the chronological sequence of histological changes after ligation of esophageal varices. PATIENTS AND METHODS: Autopsy specimens from six patients who received ligation of varices from nine hours to 22 months ante-mortem were evaluated for gross and microscopic changes. RESULTS: Early after ligation, the appearance was that of a polyp with its base compressed by the band. Variceal thrombosis was seen on day 2. Varying degrees of ischemic necrosis of the polyp were present on days 0-5. If the bands did not remain in situ for two days (premature loss), necrosis of the polyp and dilated variceal vessels were seen. On day 22, superficial ulcers were observed. After complete healing, fibrosis was seen in the submucosa. CONCLUSIONS: The changes seen in the present study are similar to those described in animals. The delay in ulcer healing, compared with the gross changes reported during follow-up endoscopic examinations, may be related to the severity of the underlying illness and the compromised immune status of patients in the present series.

Adult↗
PubMed2001

A Chinese patient with non-HFE-linked iron overload.

The gene for hemochromatosis (HFE) was recently identified and contains two missense mutations: C282Y and H63D. The C282Y mutation is found homozygous in approximately 85% to 90% of patients of Northern European ancestry with hereditary hemochromatosis. There are no previous reports with results of genetic testing in Chinese patients with regard to iron overload. In this case report, we describe a Chinese woman with marked hepatic iron overload that was nonfamilial, with unusual biopsy findings, in whom neither the C282Y nor the H63D mutations in HFE were found.

Aged↗
PubMed2000

Humanized xenobiotic response in mice expressing nuclear receptor SXR.

The cytochrome CYP3A gene products, expressed in mammalian liver, are essential for the metabolism of lipophilic substrates, including endogenous steroid hormones and prescription drugs. CYP3A enzymes are extremely versatile and are inducible by many of their natural and xenobiotic substrates. Consequently, they form the molecular basis for many clinical drug-drug interactions. The induction of CYP3A enzymes is species-specific, and we have postulated that it involves one or more cellular factors, or receptor-like xeno-sensors. Here we identify one such factor unequivocally as the nuclear receptor pregnenolone X receptor (PXR) and its human homologue, steroid and xenobiotic receptor (SXR). We show that targeted disruption of the mouse PXR gene abolishes induction of CYP3A by prototypic inducers such as dexamethasone or pregnenolone-16alpha-carbonitrile. In transgenic mice, an activated form of SXR causes constitutive upregulation of CYP3A gene expression and enhanced protection against toxic xenobiotic compounds. Furthermore, we show that the species origin of the receptor, rather than the promoter structure of CYP3A genes, dictates the species-specific pattern of CYP3A inducibility. Thus, we can generate 'humanized' transgenic mice that are responsive to human-specific inducers such as the antibiotic rifampicin. We conclude that SXR/PXR genes encode the primary species-specific xeno-sensors that mediate the adaptive hepatic response, and may represent the critical biochemical mechanism of human xenoprotection.

Animals↗
PubMed2000

Liver biopsy interpretation for the gastroenterologist.

Liver biopsy interpretation continues to play an integral role in diagnosis and management of most forms of liver disease. In this review, the common histopathologic features of the more commonly encountered processes, chronic hepatitis, autoimmune hepatitis, and chronic cholestatic liver diseases, are discussed. In addition, areas of ongoing investigation and controversy, including steatohepatitis and dysplasia, are reviewed. Finally, the pathology of adult metabolic liver disease, drug-induced liver disease, and various miscellaneous disease processes, including venous outflow obstruction, acute fatty liver of pregnancy, and fulminant hepatic failure, are reviewed.

Biopsy↗
PubMed2000

Positron emission tomography scanning in the evaluation of hepatocellular carcinoma.

BACKGROUND/AIMS: 18F-fluorodeoxyglucose uptake allows estimation of glucose metabolism by tumor cells using positron emission tomography (PET). We evaluated the role of PET imaging in the diagnosis of hepatocellular carcinoma. METHODS: PET images were collected after intravenous injection of 8-12 mCi of 18F-FDG in 20 patients with hepatocellular carcinoma (HCC). PET tumor activity level was assessed on a scale of 1 to 4 compared to normal liver tissue. The PET score was compared with abdominal computerized tomography (CT) scan results and between tumors of different grades and differentiation. RESULTS: Of the 20 patients studied, 11 (55%) had positive PET scans (PET score: 3 or 4) while nine (45%) were negative (PET score: 1 or 2). CT scan was positive in 18 patients (90%) and negative in two (10%). PET, however, revealed metastases in three patients that were not seen on CT. On pathological review, well-differentiated and low-grade tumors had lower PET scores. Comparison of the well-differentiated with the moderately- and poorly-differentiated tumors revealed a statistically significant difference. No statistical significance was observed between the moderately- and poorly-differentiated tumors or between different tumor grades and PET scores. CONCLUSIONS: The sensitivity of PET in diagnosis of HCC was 55% compared to 90% for CT scanning, although only PET detected some tumors (including distant metastases). Well-differentiated and low tumor grades had lower activity on PET and correspondingly lower PET scores. PET imaging may help assess tumor differentiation and may be useful in the diagnosis and staging and prognostication of HCC as an adjunct to CT.

Adult↗
PubMed2000

Repetitive self-limited acute pancreatitis induces pancreatic fibrogenesis in the mouse.

The role of repetitive acute injury in the pathogenesis of chronic pancreatitis remains unknown. To determine if repetitive injury induced by pancreatic hyperstimulation would reproduce the characteristic features of human chronic pancreatitis, acute reversible pancreatic injury was induced in mice by twice weekly cerulein treatment, 50 microg/kg/hr x 6 hr, for 10 weeks. Procollagen alpha1(I) mRNA was markedly increased by week 2. Sirius red staining of interstitial collagen demonstrated progressive accumulation of extracellular matrix surrounding acinar units and in interlobular spaces. Atrophy, transdifferentiation of acinar units to ductlike tubular complexes, and dilatation of intraacinar lumina also developed. Electron microscopy demonstrated the presence of stromal cells in areas of fibrosis with morphologic characteristics of pancreatic stellate cells. These findings demonstrate that, in a murine model, repetitive acute injury to the pancreas by hyperstimulation can reproduce the major morphological characteristics of human chronic pancreatitis.

Acute Disease↗
PubMed2000

Delayed recurrence of hepatocellular carcinoma after liver transplantation: detection of origin by chromosomal analysis.

We report on a 41-year-old man undergoing liver transplantation for chronic hepatitis C who presented 26 months later with hepatocellular carcinoma. No evidence of hepatocellular carcinoma could be found in the native liver, although features of small cell dysplasia were prominent. Although he had recurrent hepatitis C, the transplanted liver was not cirrhotic. Chromosomal analysis was used to resolve whether this was a de novo tumor or a recurrence of an unsuspected tumor present at the time of transplantation. This male patient had received a liver from a female donor, and in situ hybridization for the Y chromosome showed reactivity in the tumor but not in surrounding nontumorous liver. Thus, this is an example of the use of chromosomal analysis to resolve the origin of a tumor occurring in the transplant setting.

Adult↗
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↗
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↗