Orientador: Carlos Antonio Caramori / Resumo: A doença hepática gordurosa não alcoólica (DHGNA) é a alteração mais comum do metabolismo hepático, associada à obesidade, resistência à insulina e à síndrome metabólica. Compreende amplo espectro de alterações, que tem em comum a esteatose, em indivíduos que não consomem álcool. Além da sobrecarga de ingestão calórica, outros fatores como alterações do metabolismo do ferro podem estar relacionados à patogênese ou progressão da DHGNA. Analisamos no presente estudo as possíveis relações de marcadores do metabolismo do ferro com a intensidade das lesões hepáticas na DHGNA em indivíduos obesos. Foram estudados 88 indivíduos adultos, de ambos os gêneros, obesos (IMC > 30), com diagnóstico histológico de DHGNA, acompanhados no ambulatório de Gastroenterologia e Hepatologia da FMB-Unesp. Os marcadores do metabolismo do ferro avaliados foram: níveis séricos de ferro, ferritina e transferrina, bem como o índice de saturação da transferrina (IST). A presença e intensidade da deposição de ferro no parênquima hepático foram investigadas pelo método histoquímico do Azul da Prússia (Perls). A intensidade da esteatose e o grau de fibrose foram avaliados nas biópsias hepáticas. Dos 88 indivíduos avaliados, 31 (35,2 %) apresentaram aumento dos níveis séricos de ferritina e 12 (13,6%) apresentaram valores de IST acima de 45%. A avaliação histológica, das biópsias hepáticas, demonstrou a presença de fibrose em 48/88 casos (54,54%), sendo 21/88 (23,86%) de intensidade leve e 27/88 (30,68%) ca... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

Submitted by MARISE PEREIRA DA SILVA (msteix@fmb.unesp.br) on 2016-09-27T14:30:08Z No. of bitstreams: 1 Defesa Doutorado Marise Pereira da Silva - 2016.pdf: 2312700 bytes, checksum: 2943adfd4da085f54c9f7ba686299e2d (MD5) / Approved for entry into archive by Ana Paula Grisoto (grisotoana@reitoria.unesp.br) on 2016-09-28T18:44:37Z (GMT) No. of bitstreams: 1 silva_mp_dr_bot.pdf: 2312700 bytes, checksum: 2943adfd4da085f54c9f7ba686299e2d (MD5) / Made available in DSpace on 2016-09-28T18:44:37Z (GMT). No. of bitstreams: 1 silva_mp_dr_bot.pdf: 2312700 bytes, checksum: 2943adfd4da085f54c9f7ba686299e2d (MD5) Previous issue date: 2016-06-24 / Item merged in doublecheck by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2017-03-22T17:41:47Z Item was identical to item(s): 150213, 144099 at handle(s): http://hdl.handle.net/11449/149817, http://hdl.handle.net/11449/144224 / A doença hepática gordurosa não alcoólica (DHGNA) é a alteração mais comum do metabolismo hepático, associada à obesidade, resistência à insulina e à síndrome metabólica. Compreende amplo espectro de alterações, que tem em comum a esteatose, em indivíduos que não consomem álcool. Além da sobrecarga de ingestão calórica, outros fatores como alterações do metabolismo do ferro podem estar relacionados à patogênese ou progressão da DHGNA. Analisamos no presente estudo as possíveis relações de marcadores do metabolismo do ferro com a intensidade das lesões hepáticas na DHGNA em indivíduos obesos. Foram estudados 88 indivíduos adultos, de ambos os gêneros, obesos (IMC >30), com diagnóstico histológico de DHGNA, acompanhados no ambulatório de Gastroenterologia e Hepatologia da FMB-Unesp. Os marcadores do metabolismo do ferro avaliados foram: níveis séricos de ferro, ferritina e transferrina, bem como o índice de saturação da transferrina (IST). A presença e intensidade da deposição de ferro no parênquima hepático foram investigadas pelo método histoquímico do Azul da Prússia (Perls). A intensidade da esteatose e o grau de fibrose foram avaliados nas biópsias hepáticas. Dos 88 indivíduos avaliados, 31 (35,2 %) apresentaram aumento dos níveis séricos de ferritina e 12 (13,6%) apresentaram valores de IST acima de 45 %. A avaliação histológica, das biópsias hepáticas, demonstrou a presença de fibrose em 48/88 casos (54,54%), sendo 21/88 (23,86%) de intensidade leve e 27/88 (30,68%) casos moderada/grave. A investigação da presença de hemossiderina demonstrou depósitos granulares finos no citoplasma dos hepatócitos periportais em 17/88 biópsias (19,32%). Não houve associação da presença de hemossiderina no parênquima hepático com a intensidade da fibrose. A análise de regressão logística identificou a presença de DMT2 ou glicemia de jejum > 100, dislipidemia e a presença de inflamação mista (lobular e portal) como fatores independentemente associados com a fibrose. Os resultados do presente estudo demonstraram que a presença do ferro no parênquima hepático é discreta em indivíduos obesos com DHGNA e provavelmente provavelmente não relacionada à patogênese ou progressão das lesões hepáticas que ocorrem nesta entidade. / The nonalcoholic fatty liver disease (NAFLD) is the most common modification of hepatic metabolism associated with obesity, insulin resistance and the metabolic syndrome. It comprises wide spectrum of changes, which have in common steatosis in individuals who do not consume alcohol. Besides calorie intake overload, other factors such as iron metabolism disorders may be related to the pathogenesis or progression of NAFLD. We analyzed in the present study the possible relationship of iron metabolism markers with the severity of liver injury in NAFLD in obese individuals. 88 adult subjects were studied, of both genders, obese (BMI> 30), with histological diagnosis of NAFLD, from ambulatory of gastroenterology and hepatology - FMB-Unesp. The markers of iron metabolism evaluated were: serum iron, transferrin and ferritin as well as the transferrin saturation index (STI). The presence and intensity of iron deposition in the liver parenchyma were investigated by histochemical method of Prussian blue (Perls). The intensity of steatosis and degree of fibrosis in liver biopsies were evaluated. Of the 88 individuals evaluated, 31 (35.2%) showed increased serum ferritin levels and 12 (13.6%) presented IST values above 45%. Histological evaluation of liver biopsies showed the presence of fibrosis in 48/88 cases (54.54%) and 21/88 (23.86%) mild and 27/88 (30.68%) moderate cases /serious. The investigation showed the presence of hemosiderin deposits in fine granular cytoplasm of periportal hepatocytes in 17/88 biopsies (19.32%). There was no association between the presence of hemosiderin in the liver parenchyma with the intensity of fibrosis. Logistic regression analysis identified the presence of T2DM or fasting glucose > 100, dyslipidemia and the presence of mixed inflammation (lobular and portal) as factors independently associated with fibrosis. The results of this study demonstrated that the presence of iron in the liver parenchyma is slight in obese subjects with NAFLD and probably not related to the pathogenesis or progression of liver damage occurring in this entity.

O vÃrus da hepatite C (VHC) e a esteatose sÃo importantes causas de doenÃa hepÃtica crÃnica no mundo. Apesar de comum, a fisiopatologia da esteatose, e seu papel na progressÃo da fibrose em pacientes com VHC, permanece desconhecida. O objetivo deste trabalho foi quantificar esteatose macrovesicular e microvesicular e correlacionÃ-las com dados clÃnicos e histopatolÃgicos. O estudo analisou biÃpsias hepÃticas de pacientes portadores do VHC sem tratamento prÃvio. A fibrose e atividade necroinflamatÃria foram avaliadas segundo os escores de METAVIR e Ishak; as classificaÃÃes de Kleiner e Brunt foram utilizadas como suporte para o diagnÃstico de esteatohepatite realizado pelo patologista. Ademais, o nÃmero de hepatÃcitos com esteatose macrovesicular e esteatose microvesicular foram quantificados a partir do nÃmero total de hepatÃcitos. A fibrose e atividade necroinflamatÃria foram classificadas e semi-quantificadas. Foi encontrada associaÃÃo significante da fibrose avaliada pelo sistema de Ishak entre a esteatose macrogoticular e microgoticular (p= 0,017 e p= 0,0113, respectivamente). A atividade inflamatÃria global (classificaÃÃo Metavir ) apresentou correlaÃÃo linear com a piora da fibrose (< 0,001). A fibrose avaliada pelo sistema de Metavir se correlacionou com o IMC. A presenÃa de VHC associado à esteatohepatite apresentou correlaÃÃo significante com as mÃdias das AST/ALT, e com a fibrose de Ishak e Metavir, quando comparado aos dados dos pacientes com VHC, sem esteatohepatite (p = 0,006; p = 0,012; p = 0,0098 e p = 0,014, respectivamente). Em nosso trabalho, concluÃmos que a fibrose de Ishak esteve associado a esteatose macrogoticular e microgoticular. Igualmente, se demonstrou que a presenÃa da esteatohepatite esteve fortemente associado a fibrose. / The hepatitis C virus (HCV) and steatosis are important causes of chronic hepatic disease in the world. Although common, the pathofisiology of steatosis and its role in the progression of fibrosis in patients with HCV is uncertain. Our objective was to quantify the macrovacuolar and microvesicular steatosis and to correlate them with clinical and histophatologic data. The study included needle biopsy of the liver of patients with HCV without previous treatment. The fibrosis and necroinflammatory activity of hepatic damage by HCV were evaluated by METAVIR and Ishakâs scores; Kleinerâs and Bruntâs classification were used as a support for diagnosis of the steatohepatitis by the pathologist. Furthermore, the number of hepatocytes with the macrovacuolar and microvesicular steatosis was quantified in a total number of hepatocytes. Fibrosis and necroinflammatory activity were categorized and semi quantified. A significant association of the fibrosis was found and it was evaluated by the Ishak system between the macrogoticular and the microgoticular steatosis (p=0,017 e p= 0,0113, respectively). The global inflammatory activity (Metavir classification) has presented a linear correlation with the worsening of the fibrosis (< 0,001). The fibrosis which was evaluated by the Metavir system has been correlated with the BMI. The presence of HCV associated with the steatohepatitis has presented a significant correlation with the average of AST/ALT and with the Ishak and Metavir fibrosis, when compared to the data of the patients with HCV, without steatohepatitis (p= 0,006; p= 0,012; p= 0,0098 and p= 0,014, respectively) In our research we conclude that the Ishak fibrosis has been associated with the macrogoticular and microgoticular steatosis. Equally, it was demonstrated that the presence of the steatohepatitis was strongly associated to the fibrosis.

This study used the non-alcoholic steatohepatitis activity index (NAI), presence of fibrosis and Mallory-Denk bodies (MDBs), and quantification of glucose regulated protein 78 (GRP78) messenger ribonucleic acid (mRNA) as indicators of steatohepatitis development and recovery in the American mink (Neovison vison). Mink were fasted for 0, 1, 3, 5, or 7 days, and one group re-fed 28 days post 7-day fast. Liver NAI indicated that moderate fatty liver developed after 5 days of fasting. Liver recovery was achieved after the re-feeding period. There was no evidence of fibrosis or MDB formation. Upregulation of GRP78 was observed by day 7 of fasting indicating endoplasmic reticulum stress. This effect was greater in females. Results suggest that liver steatosis did not advance to steatohepatitis within a 7-day fast. However, should the length of fast be increased the mink may be at risk. Results also show that liver recovery from simple fatty liver is possible.

No description available.

Thesis (Ph.D.)--Indiana University, 2010. / Title from screen (viewed on July 21, 2010). Department of Cellular and Integrative Physiology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Michael Sturek, Jeffrey A. Breall, Robert V. Considine, Alexander Obukhov, Johnathan D. Tune. Includes vitae. Includes bibliographical references (leaves 212-240).

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第22664号 / 農博第2419号 / 新制||農||1080(附属図書館) / 学位論文||R2||N5295(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 菅原 達也, 教授 佐藤 健司, 教授 澤山 茂樹 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DGAM

The association between non-alcoholic fatty liver disease (NAFLD) and atrial fibrillation (AF) has been suggested by recent epidemiological studies although the results were inconsistent. This meta-analysis was conducted to summarize all available data. Methods A comprehensive literature review was conducted using MEDLINE and EMBASE database through May 2017 to identify all studies that reported the risk of AF among patients with NAFLD versus those without NAFLD. Effect estimates from each study were extracted and combined together using the random-effect, generic inverse variance method of DerSimonian and Laird. Results Of 1009 studies, 5 studies (two cross-sectional studies and three cohort studies) with 238,129 participants met the eligibility criteria and were included in the meta-analysis. The risk of AF in patients with NAFLD was significantly higher than subjects without NAFLD with the pooled risks ratio of 2.06 (95% confidence interval, 1.10–3.85). The statistical heterogeneity was high with an I2 of 78%, which was the major limitation of this meta-analysis. Conclusions A significantly increased risk of AF among patients with NAFLD was demonstrated in this study.

Indiana University-Purdue University Indianapolis (IUPUI) / CXXC finger protein 1 (CFP1) is an epigenetic regulator of H3K4 and cytosine methylation. Due to its role in establishing and maintaining methylation patterns, CFP1 determines whether DNA is found in its euchromatin or heterochromatin state and as such whether genes are transcriptionally active or inactive. In stem cells, deficiency of CFP1 results in inability to differentiate and in murine embryos it results in periimplantation death. Despite the demonstrated importance in developing tissue, the role of CFP1 in mature tissues, such as the liver, has yet to be elucidated. This study examined the role of CFP1 in maintaining liver homeostasis under conditions involving hepatocellular stress by examining liver regeneration, pregnancy-induced hepatomegaly, and non-alcoholic steatohepatitis (NASH) disease progression. The liver’s ability to recover was analyzed through liver:body mass ratios, blood serum analysis, liver histology, and qualitative observations. Deficiency of CFP1 in the livers of animals subjected to partial hepatectomies (PH) resulted in decreased liver regeneration capacity with liver mass restoration becoming significantly different starting at 48H post-PH and remaining so until 10D post-PH. This decreased regeneration appeared to be the result of reduced hepatocyte mitosis. Mouse dams lacking hepatic CFP1 mated with males expressing CFP1 displayed a proclivity for dystocia. Mice subjected to a fast food diet resulting in NASH while lacking hepatic CFP1 experienced decreased weight gain and hepatic lipid accumulation compared to their CFP1 expressing counterparts. Through these three studies, the critical role of CFP1 for the maintenance of liver homeostasis was demonstrated.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18682号 / 医博第3954号 / 新制||医||1007(附属図書館) / 31615 / 京都大学大学院医学研究科医学専攻 / (主査)教授 羽賀 博典, 教授 野田 亮, 教授 坂井 義治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM