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GRENI, FEDERICO. "Variabilità fenotipica nell'emocromatosi: studio di due potenziali modificatori genetici in PCSK7 e GNPAT." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/140994.
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Introduction and aim: Hereditary hemochromatosis (HH) is a genetic disease characterized by a progressive iron overload in different tissues. Homozygosity for the p.C282Y mutation is the most frequent genotype associated with the disease and it is directly responsible for an inappropriate production of hepcidin, the main regulator of iron homeostasis. Several evidences indicated that p.C282Y homozygous genotype has an incomplete penetrance due to the combined action of genetic and acquired modifier factors. Recently, the attention was focused on GNPAT rs11558492 and PCSK7 rs236918 single nucleotide polymorphisms (SNPs). The aim of my thesis was to analyse the role of these potential genetic modifiers in an Italian cohort of p.C282Y homozygotes.
Materials and methods: Patients: 298 patients (205 males and 93 females) and 169 healthy controls. Exclusion criteria were: alcohol intake >50 g/day in men and >30 g/day in women, chronic hepatitis, inflammatory status. SNPs genotyping was performed by ARMS-PCR or PCR-RFLP. Random samples were confirmed by direct sequencing. Patients and controls allelic and genotypic frequencies were compared to EVS database and analysed according to serum ferritin levels (SF), liver iron concentration (LIC) measured by liver biopsy or magnetic resonance, iron removed (IR) and liver fibrosis histologically assessed by Ishak score (IS). Fisher’s exact test, chi-squared test and t-test were used to perform statistical comparisons between groups and averages of considered variables.
Results: GNPAT rs11558492 analysis. Our results demonstrated that: a. allelic and genotypic frequencies were comparable among patients, controls and EVS data. No significant differences were found even considering two subgroups of males only with extreme phenotypes (SF <1000 mcg/L, IR <5 g and/or LIC <100 mcmol/g vs SF >2000 mcg/L, IR >10 g and/or LIC> 50 mcmol/g); b. according to iron indices, allelic and genotypic frequencies did not significantly differ neither among patients nor compared to controls, limited to SF; c. similarly, minor allele (G) frequency did not differ between patients with absent/mild fibrosis and patients with severe fibrosis/cirrhosis (20.5% vs 25%).
PCSK7 rs236918 analysis. Our study demonstrated that: a. minor allele (C) frequency was higher in patients with severe fibrosis/cirrhosis than in patients with absent/mild fibrosis (21.9% vs 7.1%; p=0.003); b. C-allele carriers were more likely to have worse liver staging scores than wild-type patients (OR=2.77, p=0.0018; ORmale-only=2.56, p=0.0233); c. PCSK7 genotype has a direct effect on severe fibrosis/cirrhosis (OR=3.11, p=0.0157) and a mild nonsignificant indirect effect mediated through SF and IR (mediation analysis: 22% and 28%, respectively).
Conclusions: Our results demonstrated that: a. GNPAT rs11558492 is not a major modifier of iron status in HH patients and controls, and is not associated with severe fibrosis/cirrhosis in HH patients. b. PCSK7 rs236918 C allele is a risk factor for cirrhosis development in Italian HH patients.
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Kučinskas, Laimutis. "Metabolinės kepenų ligos: Vilsono ligos ir hfe-hemochromatozės genetinė charakteristika." Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2013. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2013~D_20130621_093349-72294.
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Vilsono liga (VL) ir HFE-hemochromatozė – monogeninės, pagal Mendelio dėsnius paveldimos retos ligos. Šių ligų priežastis yra ATP7B arba HFE genų mutacijos, sukeliančios gyvybei pavojingas lėtines ligas. Šio darbo metu buvo tirti ligonių, sergančių metabolinėmis kepenų ligomis – VL ir HFE–hemochromatoze genų mutacijos, jų dažnis, ligų fenotipinės charakteristikos bei HFE geno dažniausių mutavusių alelių dažnis Lietuvos savanorių kraujo donorų populiacijoje. Buvo nustatyta, kad Rytų ir Centrinės Europos šalių populiacijoms būdinga c.3207C>A (p.His1069Gln) mutacija ATP7B gene taip pat dažniausia ir Lietuvoje. Patvirtinta, kad VL jautriausias metodas - molekulinis genetinis diagnostikos metodas. Kitiems klinikiniams laboratoriniams tyrimo metodams buvo būdingas mažesnis jautrumas. Ištyrus Lietuvos savanorius kraujo donorus nustatyta, kad HFE–hemochromatozės geno c.845G>A (p.Cys282Tyr) ir c.187C>G (p.His63Asp) mutacijų dažnis yra artimiausias Lenkijai ir kitoms Rytų ir Centrinės Europos šalims. HFE-hemochromatozės išsivystymo rizika yra 1,3 proc. Lietuvos savanoriams kraujo donorams, kurių genotipas c.[845G>A]; [845G>A] (0,1 proc. tiriamųjų) arba genotipas c.[845G>A];[187C>G], (1,2 proc. tiriamųjų). Tiriant HFE geno mutacijų paplitimą tarp skirtinguose Lietuvos etnokultūriniuose regionuose gyvenančių savanorių kraujo donorų nustatyta, kad c.845G>A mutacijos dažnis statistiškai patikimai buvo dažnesnis Žemaitijoje.Wilson’s disease (WD) and HFE-hemochromatosis are monogenic rare diseases inherited following Mendel’s laws. These diseases are caused by ATP7B or HFE gene mutations, which cause life-threatening chronic diseases. This study analyzed gene mutations in patients with metabolic liver diseases – WD and HFE–hemochromatosis, the frequency of such mutations, the phenotypic characteristics of these diseases, and the frequency of the most common mutations in the alleles of the HFE gene in the population of Lithuanian volunteer blood donors. The study showed that the ATP7B gene mutation c.3207C>A (p.His1069Gln), which is characteristic of the populations of Central and Eastern Europe, was also most common in Lithuania. The study confirmed that molecular genetic diagnostics was the most sensitive technique in detecting WD. Other clinical laboratory diagnostic techniques demonstrated lower sensitivity. The examination of Lithuanian volunteer blood donors showed that the frequency of HFE–hemochromatosis mutations c.845G>A (p.Cys282Tyr) and c.187C>G (p.His63Asp) was closest to that in Poland and other Eastern and Central European countries. The risk of developing HFE-hemochromatosis among Lithuanian volunteer blood donors with genotype c.[845G>A]; [845G>A] (0.1% of the subjects) or c.[845G>A];[187C>G] (1.2% of the subjects) was 1.3%. The analysis of the prevalence of HFE gene mutations among Lithuanian volunteer blood donors from different ethno-cultural regions of Lithuania showed that... [to full text]
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Andriopoulos, Bill. "Systemic iron distribution during hemochromatosis and inflammation." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18749.
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Juvenile hemochromatosis (JH), anemia of chronic disease (ACD) and various inflammatory conditions such as Hepatitis C and alcoholic steatohepatitis exhibit improper handling of systemic iron. Patients with JH have mutations in either the hemojuvelin (Hjv) or hepcidin genes. Hjv appears to control the levels of hepatic hepcidin, the master hormonal regulator of iron stores. Interestingly, Hjv exists in both a cellular and soluble form that is expressed primarily in the muscle and to a lesser extent in the liver. Cellular Hjv (cHjv), localized in the liver, is a GPI-anchored protein that enhances bone morphogenic protein (BMP) mediated induction of hepcidin. On the other hand, soluble Hjv (sHjv) is a negative regulator of hepatic hepcidin expression. We hypothesize that sHjv plays an important systemic role in regulating iron homeostasis. Thus, our goal was to 1) investigate the signals regulating shedding of muscle sHjv and 2) study the hormonal function of sHjv in the target liver. Surprisingly, using in vitro and in vivo models, we observed elevated release of Hjv during hemolytic conditions. Furthermore, in contrast to previously published reports, both cell culture and animal model studies reveal sHjv as a positive regulator of hepatic hepcidin. Upon induction of hepcidin expression in the liver, the hormonal peptide exerts its actions by binding and internalizing the iron exporter ferroportin in the reticuloendothelial system (RES) and duodenum. Using a co-culture system, we investigated the effects of secreted hepatic hepcidin on the iron metabolism of target monocytes. As a result, hepatic hepcidin was shown to inhibit iron export and promote iron retention within monocytes. Inappropriate levels of hepcidin, whether low or high, results in improper handling of iron stores which may potentially cause disease, on both sides of the iron spectrum. On one side of the scale, such as in hemochromatosis, inappropriately low hepcidin expression permits elevated mobL'hemochromatose juvénile (HJ), anémie de maladie chronique (ACD) et des conditions inflammatoires variées, telles que l'Hépatite C et la steatopathie de l'alcoolique démontrent la mauvaise manipulation du fer systémique. Les patients atteints de l'HJ ont des mutations dans soit, les gènes hemojuvelin (Hjv) ou hepcidine. Jusqu'à maintenant, Hjv semble contrôler les niveaux d'hepcidine hépatique, le régulateur maître pour les réserves de fer. D'autre part, l'Hjv soluble (sHjv) est un régulateur négatif d'expression d'hepcidine hépatique. Nous avons élaboré l'hypothèse que le sHjv joue un rôle systémique important dans la régulation d'homeostasie du fer. Alors, notre objectif était de 1) rechercher les signaux régulant la perte de muscle sHjv et 2) d'étudier la fonction hormonale du sHjv dans le foie cible. Étonnement, en utilisant des modèles in vitro et in vivo, nous avons observé la perte élevée de Hjv pendant des conditions hémolytiques. De plus, en contraste à des rapports précédemment publiés, les cultures cellulaires ainsi que les modèles basés sur les animaux révèlent que la sHjv et un régulateur positif d'hepcidine hépatique. Dès l'induction d'expression d'hepcidine dans le foie, la peptide hormonale exerce son action en fusionnant et en internalisant l'exportateur de fer, ferroportine dans le système réticuloendothélial (RES). En utilisant un système de co-culture, nous avons cherché les effets d'hepcidine hepatique secrété sur le métabolisme du fer de monocytes cibles. Des niveaux inappropriés de hepcidine, soit bas ou élevés, résultent dans la manipulation inappropriée des réserves de fer qui peuvent potentiellement mener à des maladies, des deux côtes du spectre de fer. D'un côté de la balance, tel que dans l'hémochromatose, des niveaux bas d'expression d'hepcidine permettent des niveaux de mobilisation élevés dans les réserves de fer du RES. La mobilisation accrue sature éventuellement s
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HOFFMAN-GLEMANE, HEDOUIN SABINE. "Hemochromatose idiopathique diagnostiquee au decours d'une yersiniose." Amiens, 1989. http://www.theses.fr/1989AMIEM021.
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Andrade, Lara Filipe Rocha. "Hereditary hemochromatosis: cellular response to oxidative stress." Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/12495.
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Mestrado em Bioquímica - Bioquímica ClínicaIron is a key element for basic cellular functions. If iron homeostasis is not maintained it may lead to iron overload. Patients with Hereditary Hemochromatosis (HH) and with the C282Y HFE mutation have a progressive severe iron overload that, if it is not treated, may lead to tissue damage, that mostly culminate in hepatic cirrhosis and carcinoma. Having in mind that tissue damage in HH may be related with oxidative stress (OS) caused by iron toxicity, it is important to understand in what way the OS defense is acting in cells from HH patients with severe forms of iron overload. Few studies have been performed concerning the eventual prooxidant state in blood cells, which bear a major source of OS. Nevertheless, in a recent study it was shown that cultured lymphocytes (LY) from HH, when compared with cultured LY from controls and patients with secondary forms of hemochromatosis, have an increased protection against chromosome instability (CI) induced by 1,2:3,4 diepoxybutane (DEB) – an OS-related alkylating agent. This suggests an adaptive response of HH cells to the high level of OS. However, it is not known yet if the same response can be observed with other sources of iron toxicity, namely in the presence of bleomycin (BLM), that acts forming a complex with non-transferrin bound iron (NTBI). In order to better understand the oxidant status of HH blood cells and the putative adaptive response of HH cells to iron toxicity, a study was performed to characterize two selected OS parameters: evaluation of reduced glutathione (GSH) depletion and of lipid peroxidation (LPO). The study was performed in red blood cells (RBC) and lymphocytes (LY), either basal and after 36h in culture, with and without induction of OS. Induction of OS was performed with DEB and with BLM. A second objective of the present work was to test if the previously observed adaptive response of HH cells to DEB-induced OS can also be observed after induction with BLM. Characterization of the OS parameters was performed in RBC and LY from 5 HH patients with severe iron overload and 6 healthy donors (HD), at day 0 and after 36h of culture, non-treated and treated with DEB or BLM. Studies of CI were performed in BLM-induced LY from the same 5 HH patients and 6 HD. The results show that RBC from HH patients, compared with those from HD, have a larger GSH depletion and more LPO, either at day 0 and after 36h in culture medium. This suggests an increased level of OS in HH RBC. On the contrary, LY from HH patients present less GSH depletion after 36h of culture than LY from HD, being this effect more pronounced in DEB and BLM-treated cultures. Additionally, LPO levels were decreased in LY from HH patients after 36h of culture when compared with LY from HD. This result suggests that HH cultured LY, either non-treated or treated with DEB and BLM, have a still not completely understood mechanism of defense against OS. BLM-induced CI in cultured LY from HH patients was not different from the observed in cultured LY from HD. Therefore, we can postulate that toxicity induced by BLM did not increased CI in cells from HH patients with severe iron overload.
O ferro é um dos elementos chave para as funções celulares básicas. Se a sua homeostasia não for corretamente mantida, poderá ocorrer uma sobrecarga de ferro no organismo. Os doentes com Hemocromatose Hereditária (HH), com a mutação C282Y no gene HFE, possuem uma progressiva e severa sobrecarga de ferro que, se não for tratada, pode levar a dano nos tecidos, podendo mesmo culminar em cirrose hepática e carcinoma. Tendo em conta que o dano tecidular pode estar associado ao stress oxidativo (OS) causado pela sobrecarga de ferro, é importante perceber de que modo atua o sistema de defesa contra o OS nas células dos doentes HH com forma severa de sobrecarga de ferro. Poucos estudos foram realizados sobre o potencial estado oxidante nas células do sangue, onde se encontra uma das maiores fontes de reações oxidativas. Contudo, num estudo recente foi demonstrado que linfócitos de doentes com HH, quando comparados com linfócitos de controlos e pacientes com formas secundárias de hemocromatose, apresentam uma maior proteção relativamente à instabilidade cromossómica (CI) induzida por 1,2:3,4 diepoxibutano (DEB) – um agente alquilante que provoca OS. Este estudo sugere uma resposta adaptativa das células HH a níveis elevados de OS. No entanto, ainda não se sabe se esta mesma resposta pode ser observada com outras fontes de toxicidade do ferro, nomeadamente na presença de bleomicina (BLM) cuja atividade depende da formação de complexos com o ferro não ligado à transferrina (NTBI). Para compreender melhor o estado oxidante das células do sangue dos doentes HH e a suposta resposta adaptativa das células dos doentes de HH à toxicidade do ferro, foi feita a análise de dois parâmetros de OS selecionados: avaliação da depleção da glutationa reduzida (GSH) e da peroxidação lipídica (LPO). Esta análise foi efetuada em eritrócitos (RBC) e linfócitos (LY), tanto no tempo 0 como passadas 36h em cultura, com ou sem indução de OS. O segundo objetivo deste trabalho foi testar se a BLM promove uma resposta adaptativa à CI comparável à que foi observada com o DEB. Tanto a caracterização dos parâmetros de OS como os estudos de CI foram efetuados em células de 5 doentes com HH, com elevada sobrecarga de ferro, e em células de 6 dadores saudáveis (HD). Os resultados mostraram que os RBC dos doentes com HH, comparativamente com os dos HD, apresentam uma maior depleção de GSH e maior LPO, quer ao dia 0 quer após 36h em meio de cultura. Estes resultados sugerem um aumento de OS nos RBC dos doentes. Contrariamente, os LY dos doentes de HH apresentaram menor depleção de GSH após 36h de cultura, sendo esta mais notória nas culturas induzidas com DEB e BLM. Adicionalmente, os níveis de LPO são menores em LY dos doentes de HH, após 36h de cultura, comparativamente com os dos HD. Isto sugere que culturas de LY, quer não-tratadas quer tratadas com DEB ou BLM, têm um algum tipo de mecanismo de defesa contra o OS, ainda não compreendido. A frequência de CI induzida por BLM em LY de doentes com HH não é significativamente diferente da observada em LY de HD, não se observando assim uma diferença na capacidade de resposta à BLM, entre células de doentes e controlos. Pode-se então concluir que a toxicidade induzida por BLM não aumenta a CI em células de doentes com HH com forma severa de sobrecarga de ferro.
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LOPEZ, JEAN-PHILIPPE. "Etude comparative des parametres biologiques et morphologiques au cours de l'evolution d'une hemochromatose genetique." Lille 2, 1994. http://www.theses.fr/1994LIL2M141.
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Hagen, Karin. "Studies on genetic hemochromatosis and the hepatotoxicity of iron /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-201-9/.
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LEFEBVRE, DENIS-POL. "Hemochromatose et chondrocalcinose : a propos de 3 cas cliniques." Reims, 1989. http://www.theses.fr/1989REIMM083.
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Gomes, Cidália Maria Teixeira. "HLA and hemochromatosis disease association in São Miguel Island." Master's thesis, Universidade de Aveiro, 2008. http://hdl.handle.net/10773/792.
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Mestrado em Biologia Molecular e CelularA hemocromatose hereditária uma doença autossómica recessiva do metabolismo do ferro, geralmente associada à mutação C282Y no gene HFE. Presume-se que a origem desta mutação tenha ocorrido por acaso no haplótipo HLA-A*03-B*07 de um indivíduo do noroeste da Europa. O presente trabalho visou caracterizar a associação entre os alelos e haplótipos dos loci HLA-A e -B com a mutação C282Y na população da ilha de São Miguel (Açores). Este estudo englobou 130 indivíduos, negativos para as mutações HFE H63D e S65C, que foram classificados em dois grupos: grupo C282Y (48 homozigóticos ou portadores da C282Y) e grupo controlo (82 dadores de sangue sem as três mutações no gene HFE). Para todos os indivíduos, foi efectuado a genotipagem HLA-A e -B por PCR-SSP e a detecção das mutações HFE por PCR-RFLP. A análise estatística revelou que quatro alelos – A*03 (p=0.003, OR=3.33), A*26 (p=0.003, OR=8.38), A*29 (p<0.001, OR=19.18) e B*45 (p=0.003, OR=8.37) – encontram-se significativamente aumentados no grupo C282Y. Os resultados demonstram, igualmente, uma associação significativa com a mutação C282Y para o haplótipo ancestral HLA-A*03-B*07 (p=0.006, OR=8.96) e dois haplótipos não ancestrais: A*02-B*58 (p<0.001, OR=19.78) e A*29-B*45 (p<0.001, OR=27.57). Além disso, outro haplótipo A*24-B*15 foi detectado por inferência directa num doente homozigótico para o HLA-A-B e para a mutação C282Y. Provavelmente, o mecanismo genético de recombinação gerou esta diversidade de haplótipos; no entanto, não se pode excluir a hipótese de uma mutação C282Y de novo no gene HFE associada ao haplótipo HLA-A*24-B*15. Em conclusão, além do haplótipo ancestral A*03-B*07, três novos haplótipos – A*02-B*58, A*24-B*15 e A*29-B*45 – sugerem estar associados à mutação C282Y na população da ilha de São Miguel. A elevada diversidade genética observada na população açoriana pode explicar a associação entre a mutação C282Y e os haplótipos HLA.
Hereditary hemochromatosis is an autosomal recessive disease of the iron metabolism, where HFE C282Y is commonly implicated. This mutation seems to have originated by chance on the HLA-A*03-B*07 haplotype in a northwestern European individual, and spread by migration. Given that recombination generates new haplotypes, the present investigation aimed to characterize the chromosomal background of C282Y in the São Miguel Island population (Azores). This study comprises 130 individuals, all negative for H63D and S65C, which were classified into two groups: 48 homozygous or carriers for C282Y, and 82 healthy individuals without these mutations. The subjects were HLA-A and -B genotyped by PCR-SSP, and HFE mutation detection was performed by PCR-RFLP. Statistical analysis revealed that four alleles – A*03 (p=0.003, OR=3.33), A*26 (p=0.003, OR=8.38), A*29 (p<0.001, OR=19.18) and B*45 (p=0.003 OR=8.37) – and the A*03-B*07 haplotype (p=0.006, OR=8.96) were significantly increased in the C282Y group. Two non-ancestral haplotypes were also significantly associated with C282Y: A*02-B*58 (p<0.001, OR=19.78) and A*29-B*45 (p<0.001, OR=27.57). This last haplotype showed the strongest association to the mutation in study, suggesting that it may be the principal hemochromatosis-haplotype in São Miguel Island population. Another haplotype – A*24-B*15 – was detected by direct inference in a C282Y and HLA-A-B homozygous patient. Recombination most probably generated these haplotypes, before or after the island settlement. However, we can not exclude the hypothesis of a recent de novo HFE C282Y mutation on the A*24-B*15 haplotype in an individual living in the São Miguel Island. Overall, in this population, besides the ancestral A*03-B*07, three new non-ancestral haplotypes – A*02-B*58, A*24-B*15 and A*29-B*45 – appear to be associated with C282Y. The association between this recessive mutation and these haplotypes undoubtedly reflects the high genetic diversity observed in the Azoreans.
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Pratiwi, Rarastoeti. "Genetic analysis of haemochromatosis and characterisation of the role of HFE in iron metabolism /." [St. Lucia, Qld.], 2000. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16204.pdf.
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Berlin, Daniel. "The role of HFE (hemochromatosis) gene mutations in sporadic Alzheimer disease /." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=78245.
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Although a central etiology for Alzheimer disease (AD) has not yet been determined, support has amassed for the notion that oxidative stress may be involved in the pathogenesis of AD. The disruption of iron homeostasis and iron's excessive deposition in AD brain tissues has received increased attention due to the metal's capacity to promote the production of harmful free radicals. Several studies have recently examined whether DNA mutations involved in the iron overload disorder, hemochromatosis, pose an increased risk of acquiring AD. However, the small sample size and low generalizability of previous studies have warranted further investigation. We genotyped 213 AD patients, 106 Mild Cognitively Impaired (MCI) individuals, and 63 Normal Elderly Control (NEC) subjects for the H63D and C282Y HFE mutations to examine whether a relationship exists between HFE gene status and AD presentation in our patient population. DNA analysis was conducted by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). We did not find any statistically significant associations between HFE gene status and the clinical, demographic, or neuropsychological aspects of AD in our patient population. Interesting trends that fell short of statistical significance included: (a) a deleterious effect of HFE mutations on motor performance, (b) an influence of H63D homozygosity on an earlier onset of cognitive decline, and (c) an influence of H63D homozygosity on an accelerated progression from MCI to AD.
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MARTINI, ISTRIA FRANCOISE. "L'hepatome au cours de l'hemochromatose : depistage et surveillance des patients traites." Aix-Marseille 2, 1990. http://www.theses.fr/1990AIX20179.
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Schaepelynck, Pauline. "La fonction gonadique dans l'hemochromatose genetique musculine : etude d'une serie de quinze patients." Amiens, 1990. http://www.theses.fr/1990AMIEM038.
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Bardou-Jacquet, Édouard. "Surcharges en fer rares d’origine génétique : caractérisation clinique, fonctionnelle, et biologique." Thesis, Rennes 1, 2013. http://www.theses.fr/2013REN1S156/document.
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L'hémochromatose génétique liée au gène HFE (HG) se caractérise par une augmentation de la saturation de la transferrine plasmatique, qui entraîne une surcharge en fer. Ces anomalies sont dues à une sécrétion basse d'hepcidine, le régulateur principal du métabolisme du fer, et définissent le phénotype d'hepcidino déficience. De nouvelles formes de surcharges en fer ayant un phénotype similaire ont été identifiées. Les mécanismes moléculaires en sont parfois mal compris. L'objectif général de ce travail a été de caractériser sur le plan clinique, fonctionnel, et biologique, des surcharges en fer rares d'origine génétique ayant pour point commun un phénotype d'hepcidino-déficience. Nous avons d'abord analysé une cohorte de patients porteurs d'une HG, forme type de l'hepcidino-déficience, et montré que la transplantation hépatique normalisait le métabolisme du fer, montrant ainsi le rôle majeur du foie dans le phénotype d'hepcidino-déficience de l'HG. Nous avons ensuite caractérisé des surcharges en fer à saturation de la transferrine élevée liées à des anomalies de transport du fer : i) nous avons rapporté un cinquième cas de mutations du gène DMT1 et montré le caractère pathogène de la mutation p.Asn491Ser ; ii) nous décrivons un groupe de 12 patients qui présentent une mutation hétérozygote du gène TF, l'augmentation de la saturation de la transferrine ne semblant pas être en rapport avec une hepcidino-déficience, et l'existence de cofacteurs pouvant faciliter la surcharge en fer. Nous avons ensuite décrit l'impact de mutations du gène TFR2, qui sont responsables d'une hepcidino déficience dont l'expression clinique est hétérogène mais qui peut être très précoce. Nous avons alors, pour préciser les mécanismes liant les mutations du gène TFR2 à une diminution anormale de l'hepcidine, montré in vitro que les mutations p.Asn12Ile et p.Gly430Arg altèrent l'adressage cellulaire de TFR2 tandis que la mutation p.Arg768Pro altère son interaction avec la transferrine. N'ayant pu parvenir à induire l'expression d'hepcidine sous l'effet de la transferrine, au contraire de certaines équipes mais en accord avec d'autres, nous n'avons pu analyser l'impact des mutations sur la transduction du signal liant TFR2 et hepcidine. Nos résultats contribuent à préciser les mécanismes impliqués dans l'apparition de surcharges en fer rares à saturation élevée de la transferrineHFE related hemochromatosis (HH) is characterized by an increased plasma transferrin saturation level, which causes iron overload. These anomalies are due to low hepcidin secretion, the key regulator of iron metabolism, and define the hepcidin deficiency phenotype. New forms of iron overload with similar phenotype were identified, but their molecular mechanisms remain unclear. The main objective of this work was to characterize the clinical, functional, and biological aspects of rare genetic iron overload with an hepcidin deficiency phenotype. We firstly analyzed a cohort of HH patients, archetype of hepcidin-deficiency and showed that liver transplantation cured the disease, demonstrating the major role of the liver in the phenotype. We then characterized iron overloads with high transferrin saturation related to abnormalities of iron transport: i) we reported a fifth case of patient with DMT1 gene mutations and demonstrated the pathogenicity of the mutation p.Asn491Ser; ii) we described 12 patients with heterozygous mutation of the TF gene, leading to serum transferrin decrease. The increase of transferrin saturation associated to the disease does not seem to be related to a hepcidin-deficiency, and the presence of cofactors may facilitate iron overload. We then described the impact of mutations in the TFR2 gene, which induce hepcidin-deficiency whose expression is heterogeneous but that can occur in young peoples. Then we tried to clarify in vitro the mechanisms linking mutations in the TFR2 gene to an abnormal decrease of hepcidin and showed that the p.Asn12Ile and p.Gly430Arg mutations alter the TFR2 protein intracellular trafficking while the p.Arg768Pro mutation alters its interaction with transferrin. Being unable to induce expression of hepcidin in response to transferrin, unlike some authors, but in agreement with others, we were not able to analyze the impact of mutations on signal transduction toward hepcidin. Our results help to clarify the mechanisms involved in the development of iron overload in rare high saturation of transferrin
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Kamihara-Ting, Junne. "Studies at the hemochromatosis (HFE) locus : gene conversions, haplotypes, and association analysis." Thesis, Massachusetts Institute of Technology, 2005. http://hdl.handle.net/1721.1/34193.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2006.Includes bibliographical references.
Haplotype-based association studies offer an exciting potential methodology for the identification of genes that contribute to complex traits. There is thus great interest in understanding the biological forces that shape haplotypes. We have studied a well-characterized genetic locus surrounding the gene responsible for hereditary hemochromatosis (HFE) to investigate the impact of meiotic recombination events upon haplotype structure in this region. First we identified crossover hotspots in order to define the boundaries of haplotype blocks in this locus. We then found that gene conversion events play a significant role in shaping haplotype structure within these haplotype blocks. These gene conversion events were not limited to recombination hotspots and occurred with a frequency as high as 1 in 104 per site per generation. Gene conversions lead to the creation of new haplotypes and we suggest that they are important for the spread of disease alleles in a population. In addition, we discuss how these events can be used as important tools in haplotype-based association studies. We also present an association study in a large Venezuelan cohort to search for genes that contribute to residual age of onset in Huntington's disease. We demonstrate significant association between multiple alleles in a region on chromosome 6p21.3.
(cont.) We identify two candidate genes in this region, HFE and histone Hlt and demonstrate significant association of this region with age of onset in a male-specific model.
by Junne Kamihara-Ting.
Ph.D.
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Dixon, Jeannette. "Screening for hereditary haemochromatosis : a pilot study /." [St. Lucia, Qld. : s.n.], 2002. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17400.pdf.
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Shearman, Jeremy David. "The molecular genetics of haemochromatosis." Thesis, University of Oxford, 1996. http://ora.ox.ac.uk/objects/uuid:ecb03d17-3cbf-4147-91aa-f252a2e5137e.
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Haemochromatosis is the most common single gene disorder to afflict North- West European populations. It is probably the most common genetic disorder of iron metabolism worldwide. As many as 1 in 250 people in the UK are affected and although the phenotype causes only a mild increase in gastrointestinal iron absorption a proportion of affected individuals will accumulate sufficient iron over their life-time to cause cirrhosis and hepatocellular carcinoma. Venesection treatment instituted before cirrhosis has established ensures a normal life expectancy, but clinical presentation is often late in life after irreversible organ injury has occurred. Identification of people at risk in the early, asymptomatic stage by measurements of iron status is unreliable. The genetic defect responsible for haemochromatosis has been sought in the hope that its identification might facilitate early diagnosis and that studies on the gene product would lead to a greater understanding of the mechanisms of mammalian iron absorption. Genetic linkage to HLA-A3 placed the gene responsible for haemchromatosis in, or close to, the major histocompatibilty complex (MHC) on the short arm of chromosome 6 and a positional cloning strategy has been adopted. This thesis describes work directed to the identification of the haemochromatosis gene by positional cloning. The region telomeric to the MHC was mapped using yeast artificial chromosomes, from which new microsatellites were isolated. These markers were used in linkage disequilibrium analyses and the mapping of a recombination breakpoint that defined a haemochromatosis gene region. This region was physically mapped in fine detail and positional candidates sought by EST database analysis. Before a systematic search for genes in the region began a strong positional candidate was reported (Feder et al 1996). Analysis of this mutation in patients from the UK confirmed this to be the ancestral haemochromatosis mutation.
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Chamoun, Stephanie, and Sarajlic Medina. "Genotypning av HFE c.845G>A, HFE c.187C>G och HFE c.193A>T för hemokromatos med hjälp av Realtids-Polymerase Chain Reaction : En kvalitetsutvecklande studie i Jönköpings län." Thesis, Hälsohögskolan, Högskolan i Jönköping, HHJ, Avd. för naturvetenskap och biomedicin, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:hj:diva-30788.
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Hereditär hemokromatos (HH) är en vanlig multigenetisk defekt som leder till ett onormalt förhöjt järnupptag i tarmen och ses framförallt hos kaukasisk befolkning. Sjukdomen har på senare år visats orsakats av mutationen c.845G>A men även mer ovanliga varianter som c.187C>G och c.193A>T, vilka alla finns belägna i genen HFE. HFE som finns lokaliserad intill Human Leukocyte Antigen (HLA)-genen på kromosom sex korta arm kodar för ett HFE-protein som har till uppgift att reglera kroppens järnmetabolism i interaktion med hormonet hepcidin. Vid HH avtar proteinets järnregulatoriska funktion och järnackumulation uppstår. Idag diagnostiseras HH främst via genotypning där ovanstående genvarianter påvisas. Beroende på genvariant löper individer olika hög risk för sjukdomsutveckling. I studien var syftet att verifiera det kommersiella kitet LightMix® in-vitro diagnostics kit HFE H63D S65C C282Y diagnostics kit för kvalitativ diagnostik av HFE-genotyper via Realtids-Polymerase Chain Reaction (PCR) via smältkurveanalys för eventuell införsel i rutindiagnostik. I studien kunde samtliga patientprover (n=49) ifrån Halmstad med misstänkt hemokromatos genotypas för genvarianterna i HFE-genen. Utifrån godkända resultat i prov-till-prov variation tillsammans med icke-frekventa skillnader i imprecisionstest samt 100 % samstämmighet gentemot referensmetoder på externa laboratorier, kunde slutsatsen dras att metoden är relevant för rutinverksamheten på Länssjukhuset Ryhov, Region Jönköpings Län.Hereditary hemochromatosis (HH) is a common multi-genetic defect that results in abnormally elevated iron uptake mainly in Caucasian populations. The disease has recently been found to be caused by mutation c.845G>A, in addition to the unusual variants c.187C>G and c.193A>T, all of which are detected in the gene HFE. HFE is located adjacent to the Human Leukocyte Antigen (HLA)-gene on chromosome six’s short arm and encodes for a HFE-protein, responsible for the body's iron metabolism regulation in interaction with the hormone hepcidin. As HH decreases the protein's iron-regulatory function, the iron accumulation increases. Today HH is diagnosed primarily through genotyping where variants in the HFE-gene are detected. Depending on the variant, individuals are put at varying high risk of disease development. The aim of this study was to verify the commercial LightMix® in-vitro diagnostics kit HFE H63D S65C C282Y for qualitative diagnosis of HFE-genotypes through Real-time Polymerase Chain Reaction (PCR) and melting-curve analysis for possible introduction in routine diagnostics. In the study, all samples (n=49) from patients with suspicious hemochromatosis were genotyped for the gene variants in HFE-gene. Based on all accepted results with non-frequent differences in imprecision test and 100 % consistency against the reference methods at external laboratories conclusions could be drawn that the method is applicable for routine diagnostics at the County Hospital Ryhov in Region Jönköping.
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Ducros, Marc. "Le cœur dans l'hémochromatose : intérêt de l'échocardiographie : à propos de neuf cas." Bordeaux 2, 1988. http://www.theses.fr/1988BOR25036.
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SAINT-OYANT, PHILIPPE. "L'hemochromatose perinatale : a propos d'un cas et revue de la litterature." Nice, 1992. http://www.theses.fr/1992NICE6565.
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Foucher, Karine. "Rôle de la mutation H63D du gène HFE : étude comparative de 83 sujets hétérozygotes composites C282Y/H63D et de 52 hétérozygotes simples C282Y." Montpellier 1, 1999. http://www.theses.fr/1999MON11132.
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GUYADER, DOMINIQUE. "Diagnostic de la surcharge en fer : mise au point de nouveaux marqueurs biologiques et d'imagerie." Rennes 1, 1998. http://www.theses.fr/1998REN1B027.
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COUPE, FRANCOISE. "Etude de l'immunite cellulaire dans l'hemochromatose genetique." Rennes 1, 1993. http://www.theses.fr/1993REN1M067.
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PINEAU, ANNE. "La tomodensitometrie hepatique dans la surveillance du traitement des hemochromatoses secondaires : a propos de huit dossiers." Saint-Etienne, 1990. http://www.theses.fr/1990STET6408.
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Braun, Claudine. "Traitement par saignees de l'hemochromatose idiopathique : a propos d'un cas avec disparition totale des lesions cirrhotiques." Université Louis Pasteur (Strasbourg) (1971-2008), 1991. http://www.theses.fr/1991STR1M045.
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Göhring, Claudia [Verfasser]. "Hepcidin knockout mice constitute a suitable mouse model for hereditary hemochromatosis / Claudia Göhring." Ulm : Universität Ulm. Medizinische Fakultät, 2015. http://d-nb.info/1076828523/34.
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Hallendorff, Michelle-Angelique. "Ironing out haemochromatosis : a study of an Indian family." Thesis, Stellenbosch : Stellenbosch University, 2008. http://hdl.handle.net/10019.1/21458.
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Thesis (MSc)--University of Stellenbosch, 2008.ENGLISH ABSTRACT: Iron metabolism disorders comprise the most common disorders in humans. Hereditary haemochromatosis (HH) is a common condition resulting from inappropriate iron absorption. The most common form of the disease (Type 1) is associated with mutations in the HFE gene. The C282Y homozygous genotype accounts for approximately 80% of all reported cases of HH within the Caucasian population. A second HFE mutation, H63D, is associated with less severe disease expression. The C282Y mutation is extremely rare in Asian and African populations. The H63D mutation is more prevalent and has been observed in almost all populations. Iron overload resulting from haemochromatosis is predicted to be rare in Asian Indian populations and is not associated with common HFE mutations that are responsible for HH in the Caucasian population. The aberrant genes associated with HH in India have not yet been identified. The present study attempted to identify variants in six iron regulatory genes that were resulting in the Type 1 HH phenotype observed in two Asian Indian probands from a highly consanguineous family. The promoter and coding regions of the HMOX1, HFE, HAMP, SLC40A1, CYBRD1 and HJV genes were subjected to mutation analysis. Gene fragments were amplified employing the polymerase chain reaction (PCR) and subsequently subjected to heteroduplex single-strand conformational polymorphism (HEX-SSCP) analysis. Samples displaying aberrations were then analysed using bi-directional semi-automated DNA sequencing analysis to identify any known or novel variants within the six genes. Variants disrupting restriction enzyme recognition sites were genotyped employing restriction fragment length polymorphism (RFLP) analysis. Mutation analysis of the six genes revealed 24 previously identified variants, five novel variants (HFE: 5’UTR-840T→G, CYBRD1: 5’UTR-1813C→T, 5’UTR-1452T→C, 5’UTR- 1272T→C; HJV: 5’UTR-534G→T, 5’UTR-530G→T), one previously described microsatellite and two novel repeats. Variants identified within the SLC40A1, CYBRD1 and HJV genes do not seem to be associated with the iron overload phenotype. A previously described HAMP variant (5’UTR-335G→T) was observed in the homozygous state in both probands. This variant seems to be the genetic aberration responsible for iron overload in this Indian family. The severe juvenile haemochromatosis phenotype usually associated with HAMP mutations, was not exhibited by the two Indian probands. Their symptoms resembled those observed in classic Type 1 HH. It is suggested that variants identified in the HMOX1 and HFE genes are modifying the effect of the HAMP variant and resulting in the less severe disease phenotype. Although this variant has only been identified in one Indian family, it could shed some light in the hunt for the iron-loading gene in India.
AFRIKAANSE OPSOMMING: Oorerflike hemochromatose (OH) is ‘n algemene siektetoestand wat ontstaan as gevolg van oneffektiewe opname van yster in die liggaam. Die mees algemene vorm van die siekte (Tipe 1) word geassosieer met mutasies in die HFE-geen. Die C282Y homosigotiese genotipe is verantwoordelik vir ongeveer 80% van alle gerapporteerde gevalle van OH binne die Kaukasiese bevolking. ‘n Tweede HFE mutasie, H63D, word geassosieer met minder ernstige siekte simptome. Die C282Y mutasie is besonder skaars in Asiese en Afrika bevolkings. Daar word bespiegel dat oorerflike ysteroorlading as gevolg van hemochromatose skaars is in Asiese Indiër bevolkings en word nie geassosieer met algemene HFE mutasies wat verantwoordelik is vir OH in Kaukasiese bevolkings nie. Die abnormale gene wat wél geassosieer word met OH in Indië is tot dusver nog nie identifiseer nie. Die doel van hierdie studie was om die variante in ses yster-regulerende gene te identifiseer wat die Tipe 1 OH fenotipe in hierdie familie veroorsaak. Hierdie fenotipe is waargeneem in twee Asies Indiese familielede afkomstig van ‘n bloedverwante familie. Die promotor en koderingsareas van die HMOX1, HFE, HAMP, SLC40A1, CYBRD1 en HJV gene is gesif vir mutasies. Geen fragmente is geamplifiseer met behulp van die polimerase kettingsreaksie (PKR) en daarna aan heterodupleks enkelstring konformasie polimorfisme (HEX-SSCP) analise blootgestel. PKR produkte wat variasies getoon het, is daarna geanaliseer deur tweerigting semi-geoutomatiseerde DNS volgorde-bepalingsanalise om enige bekende of nuwe variante binne die ses gene te identifiseer. Variante waar restriksie ensiem herkenningsetels teenwoordig is, is verder analiseer met behulp van die restriksie fragment lengte polimorfisme (RFLP) analise sisteem. Mutasie analise van die ses gene het 24 bekende variante, vyf nuwe variante (HFE: 5’UTR- 840T→G, CYBRD1: 5’UTR-1813C→T, 5’UTR-1452T→C, 5’UTR-1272T→C, HJV: 5’UTR-534G→T, 5’UTR-530G→T), een bekende herhaling en twee nuwe herhalings gewys. Variante wat binne die SLC4041, CYBRD1 en HJV gene geïdentifiseer is, blyk nie om by te dra tot die ysteroorladings-fenotipe nie. Die bekende HAMP variant (5’UTR-335G→T) is waargeneem in die homosigotiese toestand in beide van die aangetaste individue. Hierdie variant blyk om die genetiese fout te wees wat verantwoordelik is vir die ysteroorlading in die betrokke Indiese familie. Die erge juvenielehemochromatose fenotipe wat meestal geassosieer word met HAMP-mutasies, is nie waargeneem in hierdie familie nie. Hul simptome kom ooreen met die simptome van die klassieke Tipe 1 OH. Dit blyk moontlik te wees dat die variante identifiseer in die HMOX1 en HFE gene die impak van die HAMP variant modifiseer en die matiger siekte-fenotipe tot gevolg het. Alhoewel hierdie variant slegs in een Indiese familie geïdentifiseer is, kan dit lig werp op die soektog na die veroorsakende ysterladingsgeen in Indië.
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Gay, Choon Lin Melvin. "Development of a mass spectrometry diagnostic assay to monitor hepcidin levels in hemochromatosis patients." Thesis, Gay, Choon Lin Melvin (2010) Development of a mass spectrometry diagnostic assay to monitor hepcidin levels in hemochromatosis patients. PhD thesis, Murdoch University, 2010. https://researchrepository.murdoch.edu.au/id/eprint/4875/.
Full textAbstract:
Hepcidin has been identified as the principle regulatory peptide essential for iron homeostasis. Expression of this cysteine-rich peptide is up-regulated by inflammation and iron overload, whereas hypoxia, iron deficiency and erythropoiesis suppress hepcidin expression. The quantitative analysis of hepcidin in bodily fluids will provide an insight into the pathogenesis of disorders of iron metabolism such as hereditary hemochromatosis.
A mass spectrometry-based approach was taken to detect and quantify urinary hepcidin as urine is readily available and collection of this sample type is non-invasive. Samples were first purified using micro solid phase extraction (μSPE), followed by matrix assisted laser desorption/ionization-orthogonal-time-of-flight mass spectrometry (MALDI-TOF-MS) with inclusion of an internal standard for the quantitative analysis of unlabelled urinary hepcidin.
Monoisotopic resolution of hepcidin-25 was observed with the MALDI-TOF-MS and extraction recovery of more than 70% was achieved. Spot-to-spot variations of less than 3.5% RSD and intra- and inter-day precision of less than 9.5% RSD was observed.
In our study, average hepcidin-25 levels of 1.7 nmol/mmol creatinine were observed in healthy subjects, compared to an average of 1.1 nmol hepcidin-25/mmol creatinine in hemochromatosis patients. In one of the patients, the hepcidin level was below the detection limit (1.25 nM). From the stability experiments of hepcidin-25, it is recommended that urine samples be stored at -80oC and undergo minimal freeze-thaw cycles. It is also advised that extraction be carried out within 3 hours of thawing.
Preliminary analysis using LC-ESI-IT-MS showed multiple charge states of hepcidin-25. However, a variation of less than 5% in hepcidin-25 concentration was observed when the same sample was analyzed with both LC-MS and MALDI-TOF-MS, and thus they can be used to counter-validate each other.
In summary, a validated method has been developed for the quantification of unlabelled urinary hepcidin-25 which can be used to investigate the levels of hepcidin-25 in iron-related disorders.
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Keller, Marianne Dorothea. "New applications of MRI in toxicological research to determine in vivo changes in liver and brain /." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17517.pdf.
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Shiono, Yuhta, Hisao Hayashi, Shinnya Wakusawa, Fujiko Sanae, Toshikuni Takikawa, Motoyoshi Yano, Kenntaro Yoshioka, and Hiros Saito. "Body iron stores and Iron restoration rate in Japanese patients with chronic Hepatitis C as measured during therapeutic Iron removal revealed neither Increased body iron stores nor effects of C282y and H63d mutations on iron indices." Nagoya University School of Medicine, 2001. http://hdl.handle.net/2237/5367.
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Angel, Thierry. "L'hémochromatose idiopathique : aspects pathogéniques, cliniques et biologiques." Paris 5, 1990. http://www.theses.fr/1990PA05P087.
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Gaubert, Marie-Françoise. "Syndrome de l'homme raide et hemochromatose : etude clinique, electromyographique et approche phsysiopathologique (rapport d'une observation)." Bordeaux 2, 1988. http://www.theses.fr/1988BOR25052.
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LE, DANTEC PHILIPPE. "Les manifestations articulaires a la main et au poignet au cours de l'hemochromatose genetique : etude retrospective de 102 patients." Rennes 1, 1992. http://www.theses.fr/1992REN1M137.
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Didelot, Jean-Michel. "Enquête épidémiologique nationale sur l'hémochromatose génétique : à propos de 498 malades." Montpellier 1, 1997. http://www.theses.fr/1997MON11121.
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LABENNE, MARC. "Evaluation de la surcharge hepatique en fer dans les hemochromatoses secondaires de l'enfant : interet de la tomodensitometrie a propos de 31 malades." Besançon, 1990. http://www.theses.fr/1990BESA3069.
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Sergent, Géraldine. "Apport de l'irm hepatique au diagnostic de l'hemochromatose." Lille 2, 1992. http://www.theses.fr/1992LIL2M211.
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ABALEA, VALERIE. "Etude des dommages oxydatifs de l'adn et de leur reparation dans les hepatocytes en culture traites par le fer : effet chimioprotecteur du flavonoide myricetine (doctorat : sciences biologiques et sante)." Rennes 1, 1999. http://www.theses.fr/1999REN1BO49.
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Mortimore, Marianne. "The regulation of monocyte and macrophage iron metabolism in heriditary haemochromatosis / Marianne Mortimore." St. Lucia, Qld, 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17518.pdf.
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Young, Megan. "General practitioners' familiarity with and practices related to haemochromatosis /." [St. Lucia, Qld.], 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17037.pdf.
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Deursen, Cornelius Thomas Bernardus Maria van. "Iron content of liver tissue a biochemical, histological and clinical study, especially in hereditary haemochromatosis /." [Maastricht : Maastricht : Rijksuniversiteit Limburg] ; University Library, Maastricht University [Host], 1989. http://arno.unimaas.nl/show.cgi?fid=5456.
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Bismuth, Michaël. "Homozygotie H63D : existe-t'il un lien avec l'hémochromatose génétique et les surcharges martiales ?" Montpellier 1, 1999. http://www.theses.fr/1999MON11008.
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Ibrahim, MohD, Omer sheikh, Pratyksha Sankhyan, Qaryoute Ayah Al, Abdulrahman Ibrahim, Akilesh Mahajan, Nilesh Mahajan, Mohsen Pourmoteza, and Jason Mckinney. "Terbinafine induced fulminant hepatic failure and patient death." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/108.
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A 72 year-old-patient without known past medical history presented to the hospital with worsening cough, dyspnea on exertion, decreased appetite, weight loss for two months. Prior to admission, he was treated with a 10- day course of levofloxacin and prednisone as a case of bronchitis with minimal improvement. Then he started to develop red urine with marked changes in mental status. On physical examination, the patient had notifiable scleral icterus, confusion and abdominal tenderness in the right upper quadrant. On admission his labs were significant for alkaline phosphatase 541, aspartate transaminase 557, alanine transaminase 94, total bilirubin 8.6, lactate 11.7. CT scan of abdomen showed hepatosplenomegaly, mild ascites and trace bilateral pleural effusion. Work up with Viral hepatitis serology, cryptococcal antigen, histoplasma antigen, respiratory virus panel, Epstein Barr virus tests were negative. Anti-nuclear antibodies (ANA) and anti-mitochondrial antibody were also negative. Blood level of amylase, lipase, acetaminophen and alcohol were negative at admission too. The patient was started initially on broad spectrum antibiotics, N-acetyl cysteine empirically and aggressive intravenous fluid hydration. Patient condition rapidly worsened and he developed profound shock requiring mechanical ventilation and started on stress dose steroid and pressor support. Upon further investigation, patient was noted to take terbinafine for toe onychomycosis (day 112). Ferritin level was elevated to 1596 with 93% iron saturation. Ceruloplasmin level was normal. Patient was not a transplant candidate due to multiple organ failure. As per family request, patient was palliatively extubated and died.
Terbinafine is a fungicidal drug with activity against dermatophytes including Epidermophyton flccosum and trichophyton rubrum. It works by inhibition of squalene epoxidase with a resultant accumulation of squalene in the fungal cell and killing it as a result. Commonly used orally to treat onychomycosis and other fingernails and toenails infections. Shortly after its introduction to the market, DILI had been reported with elevation with serum aminotransferases elevation that was usually self-limited. Usually presents within first 6 weeks of therapy with either hepatocellular or cholestatic initially with sings of hypersensitivity. Mechanism of injury entails hypersensitivity reaction, though the full pathogenesis was not elucidated yet, but genetic polymorphism is implicated in the variable presentation especially among HLA-A 33:01 allele carriers. Terbinafine DILI resolves usually within 6 months of stopping the medication but can lead to death or need liver transplantation in some cases.
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KERVAIRE, ANDRE. "Apport de l'irm dans la quantification des surcharges hepatiques en fer au cours de l'hemochromatose genetique." Rennes 1, 1992. http://www.theses.fr/1992REN1M129.
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Spradling, Victoria Baird. "Phenolics in red wine pomace and their potential application in animal and human health." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/5644.
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Thesis (M.S.)--University of Missouri-Columbia, 2008.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Title from title screen of research.pdf file (viewed on August 14, 2009) Includes bibliographical references.
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YAOUANQ, JACQUELINE. "Hemochromatose genetique : etude de prevalence en bretagne, marqueurs moleculaires associes au gene et leurs applications au conseil genetique." Rennes 1, 1993. http://www.theses.fr/1993REN10164.
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L'hemochromatose est une maladie hereditaire du metabolisme du fer, transmise sur un mode recessif, et determinee par un gene (hfe) localise sur le bras court du chromosome 6, a moins d'un centimorgan du locus hla-a. La maladie induit de multiples complications et reduit l'esperance de vie mais un traitement simple entrepris precocement peut etre preventif. Dans ce travail nous avons cherche a preciser la frequence de la maladie en bretagne, a affiner la localisation du gene, et a evaluer si les nouveaux marqueurs genetiques permettaient d'ameliorer les conditions du conseil genetique: 1) l'enquete pilote de depistage menee en 1992 avec la mutualite sociale agricole d'ille et vilaine, et soutenue par l'inserm, confirme que l'hemochromatose est frequente dans la population bretonne. Sur les 5479 personnes qui se sont soumises a l'examen de sante, 2,6 pour mille ont une surcharge de fer certaine ou probable, et 4 pour mille pourraient etre homogzygotes. D'apres les donnees de mortalite de 1979 a 1983, la maladie serait trois fois plus frequente en bretagne que dans le reste de la france. Les tests de depistage actuels paraissent insuffisamment efficients pour etre proposes a titre systematique, et le depistage precoce de la maladie reste etroitement dependant de la sensibilisation des medecins, tant qu'un marqueur plus specifique n'est pas caracterise; 2) la region candidate du gene hfe a ete exploree a l'aide de sept marqueurs polymorphiques repartis sur 2000 kb de la region hla de classe i. Nous avons caracterise 151 chromosomes hfe et 182 chromosomes normaux dans 66 familles de malades, et defini des haplotypes etendus de p3a a hla-f. Un pic de desequilibre de liaison centre sur le locus hla-a suggere que la region candidate se limite a 400 kb entre i97 et hla-f. L'etude des haplotypes etendus montre que, si le gene est bien dans la zone de desequilibre de liaison, des mutations multiples sont a l'origine de la maladie en bretagne. Seule une position telomerique a hla-f serait vraiment compatible avec une mutation originelle unique. 3) dans 37 fratries de malades nous avons montre l'efficacite des polymorphismes de restriction pour identifier les sujets a risque, et ameliorer les capacites de prediction en cas d'ambiguites du typage hla. En outre, d'apres les donnees haplotypiques issues des 66 familles, nous avons defini la combinaison de marqueurs la plus performante pour obtenir un taux de prediction maximum avec un minimum de tests. Des microsatellites recemment identifies dans la region hla-a sont actuellement testes au laboratoire. Ils vont permettre d'affiner davantage la localisation du gene et, grace a leur informativite, pourront etre immediatement appliques au conseil genetique dans les familles de malades
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Varga, Daniel. "Screening of candidate genes for mutations causing hereditary hemochromatosis in patients lacking the common mutations C282Y and H63D /." [S.l.] : [s.n.], 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000277048.
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Kuek, Conchita Maria. "Hereditary haemochromatosis and the C282Y genotype : implications in diagnosis and disease." University of Western Australia. School of Surgery and Pathology, 2003. http://theses.library.uwa.edu.au/adt-WU2004.0024.
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[Truncated abstract. Please see the pdf format for the complete text.] The discovery of the C282Y mutation and its role in the development of hereditary haemochromatosis has allowed a greater understanding into the effects of iron overload and its involvement in other conditions such as diabetes and heart disease. It has also allowed the better classification of heterozygotes, who were previously only diagnosed through the use of family studies. There are however, areas of conflict between phenotyping and genotyping methods. My research involved examining the relationship between Haemochromatosis and certain diseases such as diabetes and heart disease; genotyping versus phenotyping discrepancies and the possible interaction of secondary mutations. In Chapter 3 a population study was undertaken with the aim of comparing genotyping versus phenotyping methods as well as increasing general practitioner awareness regarding hereditary haemochromatosis and its diagnosis. It was determined that a minimum of 5000 subjects would be required to give the study sufficient power. Individuals were to be between the ages of 20—40 years, and thus presumably presymptomatic. Participation was entirely voluntary and a consent form was to be signed. Recruitment of subjects proved to be difficult and there was a selective bias towards individuals already displaying symptoms of haemochromatosis. In total less than a 100 subjects were recruited for the study. There were several issues encountered in the implementation of this study. Firstly the number of GPs participating was probably insufficient to recruit the subjects required. A more extensive campaign was probably required to enroll more GPs. Secondly it is very difficult for a busy GP to find the time necessary to explain the study to each of his patients and to get them to sign the consent form. Finally a bias developed in some of the requests. The subjects participating in this study were supposed to be random but in many cases the GPs had enrolled them in the study because they had symptoms of iron overload. In effect the biggest obstacle this study faced was the recruitment of subjects. Due to the small number of subjects little statistical data could be obtained from this study. It was noted, however, that genotyping methods detected two individuals who were homozygous for the C282Y mutation. Both also had increased transferrin saturation levels. Phenotyping detected 5 individuals with increased transferrin saturation. The three others detected via phenotyping were C282Y heterozygotes. Haemochromatosis has long been though to be related to the development of diabetes due to the effect of iron overload on the pancreas. If this is so it would be logical to assume that the prevalence of haemochromatosis would be higher in a diabetic population. Chapter 4 examined the possibility that diabetics have a higher frequency of the C282Y mutation. A population group consisting of 1355 diabetics was genotyped for the C282Y mutation and iron studies were performed on all heterozygotes and C282Y homozygotes. Initial findings indicated that there was a significant difference between the diabetic and control population. However, this finding was the opposite of what was expected, there seemed to be a decreased frequency of the Y allele in the diabetic population rather than an increased one. The control and diabetic populations were not matched in terms of ethnicity. The removal of the ethnic bias in the diabetic population altered the statistics so there was no longer a significant difference between the two groups. This study highlighted the importance of using appropriate control populations as comparison groups. The final results of the study indicated that there was no significant difference between the diabetic population and the control population. This would seem to indicate that there is not an increased occurrence of the C282Y mutation in the diabetic population when compared to the control group. Chapter 5 considered the possible association between C282Y heterozygosity and cardiovascular disease as well as the potential for early mortality. Several recent studies have indicated that C282Y heterozygosity may be a risk factor for the development of atherosclerosis, possibly on the basis of increased iron loading. Using a control population and a population of individuals with known coronary events the incidence of the C282Y mutation was compared against other risk factors. C282Y heterozygosity did not appear to be a risk factor for atherosclerosis. There was however, a statistically significant link between increased ferritin in women and carotid plaques. A population of elderly women was genotyped in order to examine the effects of C282Y heterozygosity on longevity. The first hypothesis addressed in chapter 5 was that C282Y heterozygosity was a risk factor for the development of coronary heart disease.
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Bouwens, C. S. H. "Analysis of hereditary haemochromatosis and clinical correlations in the elderly." Thesis, Stellenbosch : Stellenbosch University, 2000. http://hdl.handle.net/10019.1/51584.
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Thesis (MSc)--Stellenbosch University, 2000.ENGLISH ABSTRACT: Hereditary haemochromatosis (HH) is an autosomal recessive iron storage disease where the accumulation of iron in parenchymal organs may lead to diabetes, heart failure, liver cirrhosis, arthropathy, weakness and a variety of other ailments if preventive measures are not taken. HH is often not considered as a cause of these conditions, particularly not in the elderly where the background frequencies of type II diabetes, osteoarthritis and heart failure are generally high. Heterozygosity for C282Y, the HFE-mutation causing HH in approximately 80% of affected individuals worldwide, has been linked to a raised incidence of malignancies of the colon and rectum, stomach and the haematological system. One of the highest carrier-frequencies (116) in the world for this mutation has been reported in the South-African Afrikaner population, resulting in C282Y-homozygosity in approximately 1 in every 115 people in this group. A sample of 197 elderly Afrikaner volunteers was recruited for genotype/phenotype association studies. Their clinical presentation was denoted, biochemical iron-status determined and HFE genotyping performed. Either an increase or decrease in survival, or both, were proposed, depending on possible gender effects. HH has been positively associated with various cancer types, but may also protect against iron-deficiency anaemia which is by far the most frequent cause of anaemia in the older person. This study has led to the following findings: 1. The carrier frequency of mutation C282Y was found to be 1/8 in the elderly population (similar in males and females), which is slightly lower than the 1/6 reported in younger adults from the same population. Only one C282Y homozygote and two C282YIH63D compound heterozygotes were detected, all of them female. 2. The prevalence of diabetes, heart disease, arthropathy or a combination of these conditions did not differ significantly in C282Y heterozygotes and the mutationnegative group. 3. Among 24 C282Y heterozygotes only one individual with rectal carcmoma was detected compared with two cases with rectal- and seven with colonic malignancies in 153 mutation-negative individuals. The single female C282Y homozygote identified suffered from both rectal and colon carcinoma and died approximately 6 months ago as a consequence of her colon malignancy. 4. Serum ferritin appears to be a highly unreliable parameter of iron status, particularly in the elderly where a variety of factors that may influence the levels are often present in elderly individuals. This may be due to ageing alone or as a result of multiple comorbidities. 5. Serum ferritin levels were lower than expected in elderly subjects with mutation C282Y and compound heterozygotes with both C282Y and H63D, which may be related to a variable penetrance of the HFE gene mutations. It is possible that variation in other genes exist that confer protection against iron-loading by gene-gene interaction. The probability that environmental factors (e.g. a low iron diet) are more important in this respect cannot be excluded, although this is considered less likely in the light of the fact that the same trend was observed in all mutation-positive elderly individuals. It is therefore highly likely that C282Y -positive subjects with significant iron loading have died before reaching their seventies, particularly since none of the males included in this study were homozygous or compound heterozygous for the mutations analysed. In conclusion, possession of a mutant HFE gene does not appear to confer a survival advantage in old age, neither does it seem that mutation carriers with significant ironloading are overlooked by the medical fraternity. Further investigations are warranted to shed more light on the contributions of gene-gene and gene-environment interaction in the clinical manifestation of Hll, and how these processes can be manipulated to prevent the symptoms of this largely underdiagnosed disease.
AFRIKAANSE OPSOMMING: Oorerflike hemochromatose (OH) is 'n outosomaal resessiewe yster-oorladingssiekte waar akkumulasie van yster in parenkimale organe kan lei tot suikersiekte, hartversaking, lewer sirrose, artropatie, moegheid en 'n verskeidenheid van ander probleme indien voorkomende maatreëls nie getref word nie. OH word gewoonlik nie oorweeg as moontlike oorsaak vir hierdie toestande nie, veral nie in ouer mense nie waar die agtergrond-frekwensie van tipe II diabetes, osteoartritis en hartversaking in elk geval hoog is. Heterosigositeit vir die HFE mutasie C282Y, wat OH veroorsaak in ongeveer 80% van geaffekteerde gevalle wêreldwyd, is geassosieer met 'n verhoogde voorkoms van kanker van die kolon, rektum, maag en ook die hematologiese sisteem. Van die hoogste draer frekwensies ter wêreld vir hierdie mutasie (1/6) is gevind in die Afrikaner populasie van Suid-Afrika, wat daarop dui dat 1 uit elke 115 mense in die groep homosigoties vir die C282Y mutasie kan wees. Eenhonderd sewe-en-negentig bejaarde Afrikaner vrywilligers het aan die studie deelgeneem wat daarop gemik was om genotipe/fenotipe korrelasies uit te voer. Die kliniese beeld van elke individu is gedokumenteer, die yster status biochemies bepaal en HFE genotipering uitgevoer. Die a priori veronderstelling was dat oorlewing sou toeneem of afneem, of beide, afhangende van die geslag van die individu. Daar is voorheen 'n verband gevind tussen OH en die ontwikkeling van bogenoemde maligniteite, maar aan die ander kant kan dit moontlik ook beskerm teen anemie as gevolg van yster gebrek, wat juis die mees algemene oorsaak van anemie in die ouer persoon is. Hierdie studie het tot die volgende bevindings gelei: 1. Die draer frekwensie van mutasie C282Y was 1/8 in die bejaardes (dieselfde in mans en vrouens), wat effens laer is as die 1/6 wat gerappoteer is in jonger volwassenes. Slegs een C282Y homosigoot en twee C282YIH63D saamgestelde heterosigote is opgespoor, en al drie was vroulik. 2. Die voorkoms van suikersiekte, hartsiekte, gewrigspyne of 'n kombinasie van hierdie aandoenings het nie betekenisvol verskil tussen die C282Y heterosigote en die mutasienegatiewe groep nie. 3. Daar was slegs een persoon met rektum karsinoom in die groep van 24 bejaarde C282Y heterosigote, terwyl daar twee gevalle met rektum kanker en sewe gevalle met kolon kanker gevind is onder die 153 mutasie-negatiewe individue. Die enkele vroulike C282Y homosigoot wat opgespoor is het beide rektum- en kolonkanker gehad en is ongeveer 6 maande vóór voltooing van die tesis oorlede aan haar kolon karsinoom. 4. Dit wil voorkom asof serum ferritien veral in bejaardes 'n hoogs onbetroubare maatstaf is vir yster status, aangesien dit deur 'n verskeidenheid faktore beïnvloed word wat dikwels in bejaardes aanwesig is as gevolg van veroudering of veelvuldige komorbiditeite. 5. Die serum ferritien vlakke was laer as verwag in sowel die bejaarde C282Y-homosigoot as in die twee saamgestelde heterosigote met mutasies C282Y en H63D, wat moonlik die gevolg is van die wisselende graad van penetrasie van HFE mutasies. Dit is moontlik dat variasie in ander gene beskerming bied teen yster-oorlading deur middel van geen-geen interaksie. Die moontlikheid dat omgewingsfaktore (soos 'n lae-yster dieet) 'n belangrike rol speel in hierdie verband kan nie uitgesluit word nie, hoewel dit minder waarskynlik lyk te wees in die lig van die feit dat dieselfde neiging waargeneem is in alle mutasie-positiewe bejaardes. Die kans is dus redelik groot dat individue met die C282Y mutasie en betekenisvolle yster oorlading oorlede is voordat hulle die sewentiger jare kon bereik, veral omdat geeneen van die mans wat ingesluit is in die studie homosigoot of 'n saamgestelde heterosigoot was vir die mutasies wat geanaliseer is nie. Opsommend wil dit voorkom asof die teenwoordigheid van 'n mutante HFE geen nie 'n beter oorlewingskans bied op ouer leeftyd nie, en dit blyk ook dat mutasie draers met betekenisvolle ysteroorlading nie deur dokters misgekyk word nie. Verdere navorsing is nodig om meer lig te werp op die bydrae van geen-geen- en geen-omgewing interaksie in die kliniese manifestasie van OH, en ook hoe hierdie prosesse gemanipuleer kan word om die simptome van hierdie onder -gediagnoseerde siekte te voorkom.
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Giannetti, Anthony Michael Rees Douglas C. "Biochemical, biophysical, and cellular investigations of the interactions of transferrin receptor with transferrin and the hereditary hemochromatosis protein, HFE /." Diss., Pasadena, Calif. : California Institute of Technology, 2004. http://resolver.caltech.edu/CaltechETD:etd-05262004-173612.
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Carvalho, Lya Bueno. "Avaliação da expressão da talassemia Beta no Brasil pela coherança com defeitos de hemocromatose /." São José do Rio Preto : [s.n.], 2003. http://hdl.handle.net/11449/92518.
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Orientador: Claudia Regina Bonini DomingosBanca: Ricardo Luiz Dantas Machado
Banca: Paula Rahal Liberatore
Resumo: A talassemia beta constitui um grupo heterogêneo de distúrbios genéticos da síntese de hemoglobina sendo uma das doenças monogênicas mais comums, identificada e estudada por várias décadas. É originária da região do Mediterrâneo porém, atualmente apresenta-se amplamente distribuída pelo mundo devido ao fluxo gênico pela migração das populações. No Brasil, os tipos de talassemia mais prevalentes são as talassemias alfa e beta e apresentam número variável de indivíduos portadores devido ao alto grau de miscigenação da população. As formas graves de talassemia beta são facilmente diagnosticadas entretanto, as formas mais suaves muitas vezes são interpretadas e tratadas como anemia ferropriva. O presente estudo teve como objetivo caracterizar as formas talassêmicas do tipo beta e verificar os interferentes na expressão do fenótipo como a possível co-herança com hemocromatose hereditária. Através da associação de análise hematimétrica, metodologias clássicas e análise por HPLC analisamos 332 amostras de sangue com suspeita de talassemia beta. Um total de 70 amostras foram identificadas como portadores de hemoglobinas normais (AA), 145 portadores de talassemia beta heterozigota (BTH) e 117 portadores de talassemia alfa/beta (ABT). A análise estatística por regressão linear entre as metodologias clássicas e HPLC para quantificação de hemoglobina A2 e Fetal para os três grupos foram estatisticamente significativas. A análise molecular por PCR-ASO para identificação dos mutantes para hemocromatose hereditária mostraram 11,76% de mutação C282Y e 70,58% para H63D no grupo de talassemia beta e 25% de mutação C282Y e 75% H63D para o grupo de talassemia alfa/beta. Esses resultados evidenciam a necessidade da associação de metodologias para o correto diagnóstico da talassemia beta, bem como caracterização molecular para hemocromatose...(Resumo completo, clicar acesso eletrônico abaixo)
Abstract: The beta-thalassemia constitutes a heterogeneous group of genetic disorders of hemoglobin synthesis. It has been one of the most common monogenic diseases identified and studied for many decades. Its origins are from Mediterranean region, although nowadays it is spread for the whole world due to gene flow of migration populations. In Brazil, the most prevalent types of thalassemia are the alpha-thalassemia and beta-thalassemia. They present a variable number of individual carriers due to high degree of miscigenation. The serious forms of beta-thalassemia are easily identified, but the milder forms are many times diagnosed and treated as iron deficiency anemia. The objective of the present study was to characterize the thalassemic forms and verify the interferents in the expression of the phenotype as the possible co-inheritance with hereditary hemochromatosis. It was analysed, utilizing hematimetric analysis, classic methodologies and HPLC analysis, 332 blood samples suspect of beta-thalessemia. The total of 70 samples were identified as carriers of normal hemoglobins (AA), 145 carriers of beta-thalassemia heterozigote (BTH) and 117 carriers of alpha/beta-thalassemia (ABT). The statistic analysis by linear regression between classic methodologies and HPLC for quantification of hemoglobin A2 and Fetal hemoglobin were statistically differents and significants. The molecular analysis by PCR-ASO to identify the mutants with hereditary hemochromatosis showed 11,76% of mutation C282Y and 70,58% to H63D in the beta-thalassemia group and 25% of mutation C282Y and 75% of H63D in the alpha/beta- thalassemia group. These results prove the necessity of association of methodologies in order to achieve the correct diagnosis of beta-thalassemia, as well as the molecular characterization of hemochromatosis, due to the fact of its possible co-inheritance with beta-thalassemia in the vast genotypic diversity found in Brazil.
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