Search PubMed⌕ Search

Biomedical subjects

P Brissot

Publications and source records attributed to P Brissot.

At least 19 recordsLinked to original sources
PubMed1999

Elevated parathyroid hormone 44-68 and osteoarticular changes in patients with genetic hemochromatosis.

OBJECTIVE: To determine whether the osteoarticular changes associated with genetic hemochromatosis could be explained by metabolic parathyroid hormone (PTH) disorders. METHODS: The study involved 210 patients with liver iron overload syndromes. Osteoarticular changes were numerically scored as the number of damaged joints. PTH 1-84 and 44-68 were assayed. RESULTS: An increase in serum PTH 44-68 levels was found in one-third of untreated patients who had no calcium or PTH 1-84 abnormalities. Serum PTH 44-68 levels correlated positively with serum ferritin levels. In multivariate analyses, the number of affected joints correlated positively with age, serum PTH 44-68 levels, and serum ferritin levels. CONCLUSION: Liver iron overload syndromes, especially genetic hemochromatosis, are associated with elevated circulating levels of PTH fragments containing the 44-68 region, which appears to play a role in osteoarticular changes. This increase seems to be a consequence of iron overload.

Adolescent↗
PubMed1999

Phenotypic expression of HFE mutations: a French study of 1110 unrelated iron-overloaded patients and relatives.

BACKGROUND & AIMS: Two mutations have been described in the HFE gene: C282Y and H63D. The aim of this study was to determine the phenotype of the different HFE genotypes. METHODS: Clinical symptoms and iron data were examined according to HFE genotypes in 531 unrelated patients with unexplained liver iron overload and 579 relatives of hemochromatotic patients. RESULTS: Non-C282Y +/+ patients did not markedly differ in terms of iron overload or clinical expression according to genotype, except for compound heterozygotes, who had slightly increased transferrin saturation. This contrasted with the strikingly increased expression in C282Y homozygotes. Similar phenotype/genotype correlations were observed in relatives based on serum iron test results. Family transmission of iron overload linked to HFE was exceptional in non-C282Y +/+ siblings and frequent in C282Y homozygotes. CONCLUSIONS: Iron overload in patients with the non-C282Y +/+ genotype is mild to moderate, strikingly lower than in C282Y homozygotes, and is not influenced by HFE genotype, except, to a small extent, for compound heterozygotes. The role of H63D mutation therefore seems to be marginal.

Case-Control Studies↗
PubMed1999

A genotypic study of 217 unrelated probands diagnosed as "genetic hemochromatosis" on "classical" phenotypic criteria.

BACKGROUND/AIMS: The HFE gene is a crucial candidate gene for hemochromatosis. The aims of this study were to assess the HFE genotypic profile in a large series of unrelated probands diagnosed as having phenotypic hemochromatosis, to characterize the sub-group of patients who were not homozygous for the major C282Y mutation, and to report the iron status of the detected HFE-identical siblings. METHODS: In 217 patients, the phenotypic diagnosis of hemochromatosis was based on strict bioclinical and/or histological criteria, and their genotypic profile (C282Y and H63D mutations) was determined. RESULTS: 1) 209 of the 217 probands were C282Y +/+. In 33 cases, an HFE-identical sibling was identified. Two of them had neither a clinical nor a biochemical phenotypic profile of hemochromatosis in the absence of any external factor which might have attenuated this expression. 2) Eight patients (seven males) were not C282Y +/+. Their genotypic profiles were: (C282Y +/-): six cases (four were H63D +/- and two H63D -/-); (C282Y -/-): two cases (one was H63D +/+, one H63D +/-). Phenotypic expression consisted of six cases of mild liver siderosis (among whom were the four compound heterozygotes and one case of alcoholic cirrhosis) and two severe cases of hepatic iron overload (one with alcoholic cirrhosis). Three HFE-identical siblings were identified, none of them presenting with iron excess. CONCLUSIONS: In our population: 1) The classical phenotypic criteria fitted, in 96.3% of cases, with a homogeneous genotypic entity defined by homozygosity for the C282Y mutation. Incomplete penetrance of the homozygous status was shown by the absence of the hemochromatosis phenotypic profile in 6% of the HFE-identical siblings. 2) A minority (3.7%) were not homozygous for C282Y. These were essentially men with mild iron overload, and might present with distinct iron overload entity(ies) as suggested by the presence in three of an HFE-identical sibling with absence of iron overload.

Adult↗
PubMed1999

Magnetic resonance iron-free nodules in genetic hemochromatosis.

OBJECTIVE: In hemochromatosis, areas of normal hepatic magnetic resonance (MR) signal intensity indicate the presence of iron-free-nodules, which are strongly suspected of being neoplastic. The goal of the study was to define the prevalence and the nature of these iron-free MR nodules at the time of diagnosis in 116 patients included in a prospective study assessing the accuracy of MR imaging (MRI) in the quantification of liver iron overload. METHODS: Seventy-nine of the 116 patients had homozygous hemochromatosis on a phenotypic basis. Fifteen-millimeter-thick contiguous slices were performed using T1- and T2-weighted gradient echo sequences with a 0.5 Tesla magnet. RESULTS: Six of 79 homozygous hemochromatotic patients had one or more MR iron-free nodules. Five of the six patients proved to have malignant tumors. Four of six iron-free nodules were hepatocellular carcinoma (5% in the hemochromatosis group and 17.5% in hemochromatotic patients with severe fibrosis). CONCLUSIONS: The present data confirm the high prevalence of liver cancer at the time of diagnosis, mainly in cirrhotic patients greater than 45 years of age, and indicate that, when performing MRI for liver iron quantification, a complete hepatic MRI examination is preferable to a simple signal measurement in patients at risk for hepatocellular carcinoma.

Carcinoma, Hepatocellular↗
PubMed1999

Polymorphisms in the HFE gene.

Hereditary hemochromatosis is an autosomal recessive disease characterized by progressive iron overload. Recently, a candidate gene named HFE was isolated on the short arm of the chromosome 6 within which two mutations were identified: C282Y and H63D. To date, only homozygosity for the C282Y mutation is considered as a diagnostic criterion of hemochromatosis. 7.6% of the patients studied in our laboratory did not carry two copies of the C282Y mutation. On the other hand, a dysmetabolic iron overload syndrome has recently been described and the search for the C282Y and H63D mutations revealed that none of the patients was homozygous for C282Y while 67% exhibited one of the mutations. The possibility of a new mutation in the HFE gene has been raised to explain the disease in the remaining patients, as well as, in the few hemochromatotic patients without two copies of the C282Y mutation. The aim of this study was to search for new mutations in the HFE gene in 16 such patients. Direct sequencing of exons and 3 introns did not reveal any new mutation but identified a few polymorphisms.

Alleles↗
PubMed1998

Management of hemochromatosis. Hemochromatosis Management Working Group.

The complications of iron overload in hemochromatosis can be avoided by early diagnosis and appropriate management. Therapeutic phlebotomy is used to remove excess iron and maintain low normal body iron stores, and it should be initiated in men with serum ferritin levels of 300 microg/L or more and in women with serum ferritin levels of 200 microg/L or more, regardless of the presence or absence of symptoms. Typically, therapeutic phlebotomy consists of 1) removal of 1 unit (450 to 500 mL) of blood weekly until the serum ferritin level is 10 to 20 microg/L and 2) maintenance of the serum ferritin level at 50 microg/L or less thereafter by periodic removal of blood. Hyperferritinemia attributable to iron overload is resolved by therapeutic phlebotomy. When applied before iron overload becomes severe, this treatment also prevents complications of iron overload, including hepatic cirrhosis, primary liver cancer, diabetes mellitus, hypogonadotrophic hypogonadism, joint disease, and cardiomyopathy. In patients with established iron overload disease, weakness, fatigue, increased hepatic enzyme concentrations, right upper quadrant pain, and hyperpigmentation are often substantially alleviated by therapeutic phlebotomy. Patients with liver disease, joint disease, diabetes mellitus and other endocrinopathic abnormalities, and cardiac abnormalities often require additional, specific management. Dietary management of hemochromatosis includes avoidance of medicinal iron, mineral supplements, excess vitamin C, and uncooked seafoods. This can reduce the rate of iron reaccumulation; reduce retention of nonferrous metals; and help reduce complications of liver disease, diabetes mellitus, and Vibrio infection. This comprehensive approach to the management of hemochromatosis can decrease the frequency and severity of iron overload, improve quality of life, and increase longevity.

Diet↗
PubMed1998

Antiproliferative effect of deferiprone on the Hep G2 cell line.

Iron is an essential element in cellular metabolism and the growth of all living species, and is involved in DNA replication. The risk of hepatocellular carcinoma development is associated with an increase in iron availability. The aim of the present work was to investigate the effect of an oral iron chelator, deferiprone (CP20), on HepG2 cell-line proliferation in culture. HepG2 cell cultures were maintained in the absence of fetal calf serum (FCS) and in the presence or not (control cultures) of CP20 at the concentrations of 50 or 100 microM; deferoxamine (DFO) was used as an iron chelator reference. Cell proliferation was investigated by the analysis of DNA synthesis using [3H] methyl-thymidine incorporation and of the cell cycle by flow cytometry. Iron chelation efficiency in the culture model was studied by analyzing the effect of CP20 on radioactive iron uptake, intracellular ferritin level, and transferrin receptor expression. CP20, at the concentration of 50 or 100 microM, inhibited DNA synthesis after 48 hr of incubation and induced an accumulation of the cells in the S phase of the cell cycle. Iron chelators inhibited cellular iron uptake, decreased intracellular ferritin level, and increased transferrin receptor protein and mRNA levels. Our results show that CP20 as well as deferoxamine inhibit HepG2 cell proliferation and block cell cycle in the S phase.

Cell Cycle↗
PubMed1998

Iron mobilisation and cellular protection by a new synthetic chelator O-Trensox.

We tested a new synthetic, 8-hydroxyquinoline-based, hexadentate iron chelator, O-Trensox and compared it with desferrioxamine B (DFO). Iron mobilisation was evaluated: (i) in vitro by using ferritin and haemosiderin; DFO mobilised iron much more rapidly from ferritin at pH 7.4 than did O-Trensox, whereas at pH 4, ferritin and haemosiderin iron mobilisation was very similar with both chelators; (ii) in vitro by using cultured rat hepatocytes which had been loaded with 55Fe-ferritin; here DFO was slightly more effective after 100 hr than O-Trensox; (iii) in vivo administration i.p. to rats which had been iron-loaded with iron dextran; O-Trensox mobilised 51.5% of hepatic iron over two weeks compared to 48.8% for DFO. We also demonstrated the effect of O-Trensox in decreasing the entry of 55Fe citrate into hepatocyte cultures. The protective effect of O-Trensox against iron toxicity induced in hepatocyte cultures by ferric citrate was shown by decreased release of the enzymes lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotranferase (ALT) from the cultures and, using electron paramagnetic resonance (EPR) measurements, decreased production of lipid radicals. O-Trensox was more effective than DFO in quenching hydroxyl radicals in an acellular system.

Animals↗
PubMed1998

A point mutation in the bulge of the iron-responsive element of the L ferritin gene in two families with the hereditary hyperferritinemia-cataract syndrome.

The molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome is the presence of a mutation in the iron-responsive element (IRE) of the L ferritin gene, located on chromosome 19q13.3-13.4. Two mutations have been reported so far, altering adjacent nucleotides in the IRE loop, in a region that has been extensively studied in vitro and shown to mediate high affinity interaction with the iron-responsive protein. In this report, we describe two families with a new mutation in the bulge of the IRE stem, and we show that this mutation alters the protein-binding affinity of the IRE in vitro to the same extent as the loop mutation. In addition, we present evidence that some variability in the age of onset of cataract can be associated with this genetic syndrome, probably because of additional genetic or environmental factors that modulate the penetrance of the L ferritin defect in the lens. We confirm that the patients do not have increased iron stores despite the persistence of elevated serum ferritin levels and that, accordingly, they do not tolerate well venesection therapy. Further studies will be necessary to elucidate the mechanism responsible for the onset of cataract.

Adult↗
PubMed1998

Noninvasive prediction of fibrosis in C282Y homozygous hemochromatosis.

BACKGROUND & AIMS: The diagnosis of hemochromatosis is now possible for C282Y homozygous patients using noninvasive molecular genetic tests. The aim of this study was to define noninvasive factors predictive of severe fibrosis (bridging fibrosis or cirrhosis) to avoid unnecessary liver biopsies in such patients. METHODS: Clinical and biological data were recorded at the time of diagnosis in 197 French C282Y homozygous patients, 52 (26%) of whom had severe fibrosis. Variables significantly linked to severe fibrosis using univariate analysis were entered into a multivariate stepwise analysis. These variables were combined to obtain a simple index allowing for prediction of severe fibrosis. RESULTS: Serum ferritin, hepatomegaly, and serum aspartate aminotransferase were selected using multivariate analysis. Their combination applied to the 96 patients with ferritin level of </=1000 microgram/L, normal aspartate aminotransferase values, and absence of hepatomegaly showed that no severe fibrosis was encountered in this subgroup of patients. The results were validated in 113 C282Y homozygous patients in Canada with a good reproducibility of negative prediction but a poor reproducibility of the positive prediction of severe fibrosis. CONCLUSIONS: In C282Y homozygous patients, the diagnosis of severe fibrosis relies on liver biopsy, but absence of severe fibrosis can be accurately predicted in most patients on the basis of simple clinical and biochemical variables.

Adult↗
PubMed1998

Deferoxamine arrests in vitro the proliferation of porcine hepatocyte in G1 phase of the cell cycle.

Iron is required for cell proliferation of all living species. Moreover, iron excess may be involved in the development of hepatocellular carcinoma. In this study we analyzed the effects of deferoxamine, an iron chelator, on normal porcine hepatocyte proliferation. We confirmed that hepatocytes isolated from young pigs proliferate in the presence of insulin and fetal calf serum as shown by [3H] methyl-thymidine incorporation, presence of mitotic figures and increase in cell number. This was paralleled by nuclear expression of p34cdc2 and its associated histone H1 kinase activity. In the presence of deferoxamine, [3H] methyl-thymidine incorporation, expression of nuclear proteins (p34cdc2 and PCNA) and H1 kinase activity were drastically reduced. In addition, in contrast with control cultures, cells in S-phase were not detected by flow cytometry. These data suggest that iron chelation by deferoxamine can arrest the progression of porcine hepatocytes in the G1 phase of the cell cycle.

Animals↗
PubMed1998

In vitro demonstration of synergy between radionuclide and chemotherapy.

UNLABELLED: Radionuclide therapy is currently used in the treatment of some malignancies, including hepatocellular carcinoma. The effects of external beam radiotherapy are improved by combining it with chemotherapy. The aim of this study was to determine whether such a synergistic effect could be demonstrated in vitro with internal radiation therapy. METHODS: HepG2 cells were cultured from Day 0 to Day 8 under the following conditions: exposure for 4 hr on Day 2 to increasing concentrations of 5-fluorouracil (5FU), doxorubicin or cisplatin (CDDP); exposure from Day 2 to Day 8 to increasing concentrations of 131-iodide; exposure on Day 2 to low-toxicity doses of drugs for 4 hr, followed by exposure to 131I at increasing concentrations; and exposure to increasing concentrations of 131I from Day 2 to Day 8, with exposure for 4 hr on Day 6 to the drugs. Cell toxicity was assessed by enzyme release (lactate dehydrogenase and aspartate aminotransferase) in the culture medium and on cell survival (protein and tetrazolium dye test). All cultures were run in triplicate. RESULTS: A dose- and time-dependent toxicity was demonstrated with doxorubicin and CDDP but not with 5FU. When HepG2 cells were exposed to 131I, the toxicity was rather low, but significant, and was time- and dose-dependent. Treating these cells with combination radiotherapy and chemotherapy resulted in a toxicity that was significantly greater than that with 131I or chemotherapy drugs alone. CONCLUSION: The radiosensitivity of HepG2 cells is low; combining a chemotherapeutic drug with a radiotherapeutic agent improves the radiosensitivity in a synergistic fashion. This combination is thus able to strengthen the therapeutic effect of internal radiation therapy in different malignancies, particularly in hepatocellular carcinoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

[Epidemiology of hepatitis C virus infection in 1,304 HCV positive patients: variations according to the origin of transmission and year of diagnosis].

UNLABELLED: The evolution of epidemiological data on hepatitis C virus infection is poorly documented and thus the impact of screening is difficult to evaluate. AIM: To study epidemiological variations based on the origin of transmission and the year of diagnosis of hepatitis C virus infection. METHODS: The files of all 1304 patients seen in the hepatology unit of the Rennes University Hospital were analyzed (retrospectively before and prospectively after October 1995) in relation to epidemiological features. RESULTS: Despite widespread screening which is the source of 60% of the diagnoses, the total number of new cases of hepatitis C infection per year has not increased. Compared to patients diagnosed in the first years following the discovery of the virus, patients recently identified were younger (42 +/- 14 years) and frequently drug addicts (40%). Aminotransaminases were normal in 20% of cases. The frequency of cirrhosis has declined (17%). There has been a decrease in the proportion of patients who undergo liver biopsy (50%) and treatment with interferon (one third of patients). CONCLUSIONS: The impact of screening on the number of newly treated patients seems to be lower than previously predicted.

Adult↗