nÃo hà / IntroduÃÃo: A esteatohepatite nÃo alcoÃlica (NASH) à um evento adverso do quimioterÃpico irinotecano extremamente relevante, pois associa-se a uma maior mortalidade apÃs ressecÃÃes hepÃticas. Atà o momento nÃo hà na literatura um modelo experimental bem estabelecido de NASH induzido por irinotecano. Objetivo: Estabelecer um modelo experimental de NASH induzida pelo irinotecano em camundongos que simule os aspectos histopatolÃgicos encontrados na clÃnica. Estudar os mecanismos e mediadores envolvidos na sua fisiopatologia incluindo citocinas inflamatÃrias, estresse oxidativo e participaÃÃo da translocaÃÃo bacteriana intestinal. MÃtodos: Camundongos machos do tipo Swiss, pesando entre 25 a 30g,foram divididos em grupos experimentais (n=8-10) e foram injetados com soluÃÃo salina (5 mL/kg, i.p.) ou Irinotecano nas doses 25, 50, 75 or 100 mg/kg, i.p, trÃs vezes por semana em dias alternados. Os animais foram entÃo pesados e sacrificados ao fim das semanas 1, 3, 5, 7 e 9. No sangue foram dosados os nÃveis de ALT e AST, leucograma, proteÃnas totais e realizada hemocultura da veia porta e do plexo ocular. Nas amostras do tecido hepÃtico, avaliaram-se os nÃveis de lipÃdeos totais, mieloperoxidase, malonaldeÃdo e glutationa (GSNP) seguida da anÃlise histopatolÃgica realizada apÃs preparaÃÃo da lÃmina pelos mÃtodos HE e Masson para avaliar e graduar os critÃrios histolÃgicos da NASH. As amostras de duodeno foram examinadas histologicamente (HE) para graduar a mucosite. ImunohistoquÃmica para IL-1, IL-18, NOSi, TNFα e TLR-4 foi realizada tanto nas amostras hepÃticas como duodenais. A anÃlise estatÃstica foi realizada empregando o teste t de Student para variÃveis nÃo pareadas ou o teste Mann-Whitney quando indicado. Resultados: A dose de 50mg/kg de irinotecano trÃs vezes por semana i.p. (IRI 50) se associou com perda de peso, leucopenia, hepatomegalia, diminuiÃÃo das proteÃnas plasmÃticas e aumento das enzimas hepÃticas (ALT e AST). IRI 50 alterou os parÃmetros de estresse oxidativo, elevando a expressÃo de malonaldeÃdo e diminuindo GSNP com inÃcio na primeira semana do experimento. IRI 50 tambÃm se associou a todas as alteraÃÃes histolÃgicas da NASH (esteatose, infiltraÃÃo neutrofÃlica e tumefaÃÃo celular e fibrose) analisadas na sÃtima semana quando comparado com controle salina. Nas amostras duodenais, observamos alteraÃÃes histolÃgicas de mucosite severa a partir da terceira semana. Houve tambÃm em IRI 50 aumento da imunoexpressÃo de IL-1, NOSi e TLR-4 tanto nas amostras do fÃgado como nas do duodeno na semana 7. Nas hemoculturas de sangue portal e orbitÃrio identificou-se o crescimento de enterobactÃrias gram-negativas desda a primeira semana do experimento. ConclusÃo: A administraÃÃo de irinotecano 50mg/kg i.p. trÃs vezes por semana por sete semanas consecutivas à um modelo experimental que reproduz todas as alteraÃÃes histopatolÃgicas da NASH induzida por irinotecano observadas na clÃnica. Existem evidÃncias da participaÃÃo concomitante das citocinas inflamatÃrias e do estresse oxidativo na patogÃnese da NASH em nosso modelo. A translocaÃÃo bacteriana intestinal com bacteremia portal por gram-negativos pode ser o insulto primeiro e o elo de conexÃo comum entre os diversos fatores fisiopatolÃgicos. / Introduction: The nonalcoholic steatohepatitis (NASH) is a relevant adverse effect of the chemotherapy with irinotecan, since it has been associated with increased surgical mortality after hepatic resections. So far there are no reports in the literature of a well established experimental irinotecan-induced NASH model. Aim: Develop an experimental model of irinotecan-induced NASH in mice that simulate the full histological alterations found in the clinical practice. Study the possible mechanisms and mediators involved into its pathophysiology including inflammatory cytokines, oxidative stress and the participation of intestinal bacterial translocation. Methods: Male swiss mice weighting between 35 and 30g were divided into experimental groups (n=8-10) and were injected with saline (5 mL/kg, i.p.) or irinotecan in the following dosages: 25, 50, 75 or 100 mg/kg, i.p, three times a week every other day. Mice were weighted and killed at the end of the weeks 1, 3, 5, 7 and 9. Measurements of ALT and AST, leukocytes, total proteins were performed in blood samples as well as cultures of portal vein and ocular plexus blood. In the hepatic tissue samples, total lipids, myeloperoxidase, malonaldehyde and nonproteic sulfidryl groups (NPSH) levels were analyzed, followed by histological evaluation, after slide preparation through HE and Masson methods. Duodenal samples were examined histologically for mucositis grading. Immunohistochemistry analysis for IL-1, IL-18, NOSi, TNFα e TLR-4 were performed in both hepatic and duodenal tissue samples. Statistical analysis was carried out through Studentâs t test or Mann-Whitney test, as indicated. Results: The dose of 50mg/kg of irinotecan three times a week i.p. (IRI 50) associated to weight loss, low white cell count, hepatomegaly, decreased total plasma proteins and elevated hepatic enzymes (AST and ALT). IRI 50 altered oxidative stress parameters, elevating elevating malonaldehyde and decreasing NSPG levels at hepatic tissue starting at week 1. IRI 50 also was associated to the full histological changes found in NASH (steatosis, neutrophilic infiltration and hepatocyte balloning) when analyzed at the seventh week and compared to saline group. The duodenal samples showed severe mucositis changes starting at week three. It was also demonstrated elevated immunostaining for IL-1, iNOS and TLR-4 in both liver and duodenal samples at week seven. The cultures were positive for gram negative intestinal bacteria in portal and orbital blood since the first experimental week. Conclusion: The administration of the irinotecan 50mg/kg i.p. three times a week for seven consecutive weeks is an experimental model that reproduces all the histological changes found in the irinotecan-associated NASH found in clinical practice. Concomitant participation of inflammatory cytokines and oxidative stress were found to play a role in NASH pathogenesis in this model. Intestinal gram-negative bacterial translocation leading to portal bacteremia may represent the very first hepatic insult and the connection between the pathogenic factors.

Background/objectives The relationship between nonalcoholic fatty liver disease (NAFLD) and albuminuria has been shown in many epidemiologic studies, although the results were inconsistent. This meta-analysis was conducted to summarize all available data and to estimate the risk of albuminuria among patients with NAFLD. Methods Comprehensive literature review was conducted utilizing Medline and Embase database through January 2018 to identify studies that compared the risk of albuminuria among patients with NAFLD versus those without NAFLD. Effect estimates from each study were extracted and combined using the random-effect, generic inverse variance method of DerSimonian and Laird. Results Nineteen studies (17 cross-sectional studies and two cohort studies) with 24 804 participants fulfilled the eligibility criteria and were included in this meta-analysis. The risk of albuminuria among patients with NAFLD was significantly higher than those without NAFLD with the pooled odds ratio (OR) of 1.67 [95% confidence interval (CI): 1.32-2.11]. Subgroup analysis demonstrated the significantly increased risk of albuminuria among patients with NAFLD without diabetes with pooled OR of 2.25 (95% CI: 1.65-3.06). However, we found no significant association between albuminuria and NAFLD among diabetic patients [pooled OR 1.28 (95% CI: 0.94-1.75)]. Conclusion A significantly increased risk of albuminuria among patients with NAFLD was observed in this meta-analysis. Physicians should pay more attention to the early detection and subsequent treatment of individuals with microalbuminuria especially in patients with NAFLD.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第18147号 / 医博第3867号 / 新制||医||1002(附属図書館) / 31005 / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 坂井 義治, 教授 千葉 勉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DGAM

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Die Nicht-alkoholische Steatohepatitis (NASH), gehörig zu der Gruppe der chronischen Lebererkrankungen als eine schwere Form der Nicht-alkoholischen Fettleber-erkrankungen (NAFLD), nimmt in ihrer Prävalenz ständig zu. Gründe dafür sind u.a. eine gesteigerte Nahrungsaufnahme sowie Veränderungen der Nahrungszusammen-setzung. Es kommt zur Ausbildung einer Steatose, die sich unter Mitwirkung verschie-dener Einflussfaktoren zur Steatohepatitis weiterentwickeln kann, wobei die Pathoge-nese noch nicht genau verstanden ist. Die Nicht-alkoholische Steatohepatitis geht oft einher mit Insulinresistenz und starkem Übergewicht. Die Folgen für die Leber sind Funktionseinschränkungen und –verlust, hervorgerufen durch eine massive Akkumula-tion von Triglyzeriden in den Hepatozyten, Entzündungsprozesse sowie einem fibro-tischen Umbau der Leber. Im fortgeschritten Stadium wird eine Lebertransplantation unausweichlich, die jedoch aufgrund des zunehmenden Mangels an Spenderorganen oft nicht möglich ist. Eine Alternative bietet die Transplantation mesenchymaler Stammzellen (MSC). MSC können in vitro in leberzellähnliche Zellen differenziert wer-den und weisen dabei essentielle hepatozytäre Eigenschaften auf, wodurch sie als möglicher Ersatz bzw. als Überbrückungstherapie bis zur Lebertransplantation in Frage kommen. Die vorliegende Arbeit beschäftigte sich mit dieser Fragestellung. Dazu wur-de ein Tiermodell der NASH mittels Methionin-Cholin-defizienter Diät (MCD-Diät) etab-liert und die Transplantation von hepatozytär differenzierten MSC durchgeführt. An-hand spezifischer zellulärer und biochemischer Marker der NASH konnte die Wirkung des Zelltransplantats auf die Empfängerleber analysiert werden. Es hat sich gezeigt, dass die MSC einen anti-inflammatorischen, anti-fibrotischen und pro-proliferativen Einfluss auf das Empfängerparenchym hatten und somit zur Verbesserung der Symptomatik der NASH beitrugen.

To evaluate the suitability of volume index measurement (VI) by either ultrasound (US) or computed tomography (CT) for the assessment of liver volume. Fifty-nine patients, 21 women, with a mean age of 66.8 ± 12.6 years underwent US of the liver followed immediately by abdominal CT. In US and CT imaging dorsoventral, mediolateral and craniocaudal liver diameters in their maximum extensions were assessed by two observers. VI was calculated by multiplication of the diameters divided by a constant (3.6). The liver volume determined by a manual segmentation in CT (“true liver volume”) served as gold standard. True liver volume and calculated VI determined by US and CT were compared using Bland–Altman analysis. Mean differences of VI between observers were − 34.7% (− 90.1%; 20.7%) for the US-based and 1.1% (− 16.1%; 18.2%) for the CT-based technique, respectively. Liver volumes determined by semi-automated segmentation, US-based VI and CT-based VI, were as follows: 1.500 ± 347cm3; 863 ± 371cm3; 1.509 ± 432cm3. Results showed a great discrepancy between US-based VI and true liver volume with a mean bias of 58.3 ± 66.9%, and high agreement between CT-based VI and true liver volume with a low mean difference of 4.4 ± 28.3%. Volume index based on CT diameters is a reliable, fast and simple approach for estimating liver volume and can therefore be recommended for clinical practice. The usage of US-based volume index for assessment of liver volume should not be used due to its low accuracy of US in measurement of liver diameters.

Thesis (PhD (Medicine. Internal Medicine))--Stellenbosch University, 2008. / Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease in Western countries, extending from steatosis (FLD) to steatohepatitis (NASH). Differentiation between NASH and nonprogressive NAFLD is difficult on clinical grounds therefore a need exists to identify reliable biomarkers of disease progression. The aims of the study were 1) to describe the disease profile of NAFLD/NASH in South African patients of the Western Cape, 2) to investigate the metabolic derangements associated with this condition, including insulin resistance, lipid abnormalities and liver fibrogenesis, and 3) to assess the possible involvement of candidate genes in relation to the disease phenotype in the patient cohort. A total of 233 patients (73% female) were enrolled in this study, consisting of 69% Cape Coloured, 25% Caucasian, 5% Black and 1% Asian individuals. All subjects were obese or overweight based on the assessment of body mass index (BMI). Screening for NAFLD identified 182 patients (87%) with ultrasonographical evidence of fatty infiltration and/or hepatomegaly. Liver biopsies were performed on patients with persistently abnormal liver functions and/or hepatomegaly. NAFLD was confirmed histologically in 111 patients of whom 36% had NASH and 17% advanced liver fibrosis. None of the Black patients had advanced fibrosis.

The body encounters an innumerable amount of foreign substances, termed xenobiotics, which it must remove in order to prevent damage to cells and organs. This system of removal is a collection of processes known as ADME (absorption, distribution, metabolism, and excretion). The dynamics of ADME ultimately determine the fate, or pharmacokinetics, of a xenobiotic in the body whether it be an administered pharmaceutical or a potentially harmful toxicant. The major cellular effectors of ADME are the drug metabolizing enzymes (DMEs) and transporters. DMEs function to transform xenobiotics into a metabolite that is more suitable for excretion, whereas drug transporters serve a two-fold function. They may facilitate the uptake of the xenobiotic into the cell so that it can be acted upon by DMEs, or they may function to actively secrete xenobiotics and metabolites from the cell, encouraging their removal from the body. Any perturbations in the expression or function of these critical cellular effectors can result in the diminished therapeutic effect of a pharmaceutical via accelerated removal from the body, or increased toxicity of a pharmaceutical or toxicant due to retention in the body and increased exposure.Perturbations in the ADME processes may result in adverse drug reactions (ADRs) which are an unintended response to a pharmaceutical when administered at the recommended dose. In the last reporting year, the USFDA documented 471,291 serious ADRs causing hospitalization or permanent disabilities, of which 82,724 resulted in death. ADRs can be categorized as two types: dose-related ADRs, and those that are generally unpredictable and mostly occur in susceptible individuals. The major factors that make a person susceptible to ADRs are genetics and disease; however, genetics account for only a small proportion. This dissertation is focused on the contribution of an environmentally-derived component, particularly liver disease, to the occurrence of ADRs. Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease of industrialized nations. It represents a spectrum of damage progressing to the severe stage of nonalcoholic steatohepatitis (NASH), and is closely related to obesity and type 2 diabetes. The following studies have determined the effect of NAFLD and NASH on DMEs and transporters, and demonstrated the propensity for NASH to result in serious ADRs.

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%) caso... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor