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Measuring the amount of bromsulfophthalein (BSP) retained in serum 30 minutes after intravenous injection can be used to evaluate hepatic function. BSP retention of less than 5% 30 minutes after intravenous administration is considered normal in dogs. The BSP retention test fell out of favor due to perceived inaccuracy when compared with bile acid and ammonia testing and a fear of hypersensitivity reactions. BSP was discontinued as a commercially-available drug in 1984. Use of BSP has continued at virginia tech despite the test's reputed disadvantages. The purpose of this study was to evaluate the efficacy of the BSP retention test in dogs with and without histopathologically-confirmed hepatobiliary disease. The medical records of 150 dogs with hepatobiliary disease having both a BSP retention test and hepatic biopsy performed were evaluated. Histopathologic slides were reviewed, and dogs were classified according to one of 11 predetermined histopathologic categories. Twenty-five random-source dogs were used as controls. Adverse effects following BSP administration were not observed in any dog. BSP retention was significantly different between hospitalized and control dogs, but the test could not distinguish between dogs with different types of hepatobiliary disease. Sensitivity, specificity, and predictive values of the BSP retention test were calculated, and its sensitivity was comparable to that of serum bile acid and ammonia testing. Using 6.0% retention as a cut-off for normal retention resulted in a specificity of 100%, sensitivity of 69.8%, positive predictive value of 100%, and negative predictive value of 35.7%. / Master of Science

Obesity and insulin resistance are associated with a constellation of features including hypertension, dyslipidaemia, type 2 diabetes, and premature cardiovascular disease, collectively termed the metabolic syndrome. Non-alcoholic fatty liver disease (NAFLD) represents the hepatic component of this syndrome, incorporating a spectrum of liver disease with increasing morbidity and mortality, from simple steatosis, to non-alcoholic steatohepatitis (or NASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma. However, factors influencing this progression are incompletely understood. In this thesis I sought to investigate pathways which promote hepatic inflammation and fibrosis by studying two contrasting dietary models of NAFLD in mice in which the risk of hepatic inflammation, insulin resistance and fibrosis differ; namely the methionine and choline deficient diet (MCDD) which induces steatohepatitis, hepatic insulin resistance, and weight loss, and the choline deficient diet (CDD) which may be protected from insulin resistance, and leads to steatosis without inflammation or weight loss. I investigated the possible molecular mechanisms underlying these differences, and whether they influenced progression to hepatic fibrosis induced by carbon tetrachloride (CCl4).

O objetivo do presente trabalho foi avaliar o valor diagnóstico e o impacto na modificação da conduta terapêutica do ultra-som intra-operatório (UIO) na cirurgia por neoplasia de fígado, vias biliares e pâncreas, comparando-se achados da avaliação pré-operatória de rotina com métodos de imagem convencionais (tomografia computadorizada e ressonância magnética) com achados obtidos por meio da exploração cirúrgica (inspeção e palpação). Foram analisados, retrospectivamente, exames realizados em 49 pacientes, sendo 15 portadores de neoplasia hepática secundária; 14, de neoplasia hepática primária; 14, de tumor neuroendócrino pancreático e seis de neoplasia cística pancreática. No grupo de pacientes com neoplasia hepática e de vias biliares, a TC identificou 65% dos tumores; a exploração cirúrgica, 69,5% e o UIO, 95,2%. Houve mudança da conduta, em decorrência dos achados do UIO, em 34,4% dos pacientes. No grupo de tumores neuroendócrinos pancreáticos, a TC identificou corretamente 44,4% dos tumores; a RM, 60,9%; a exploração cirúrgica com palpação, 72,7% e o UIO, 100%. Houve mudança de conduta em 42,9% dos pacientes. No grupo de neoplasia cística, o UIO não acrescentou informação adicional relevante em relação à TC e à RM, exceto no paciente com neoplasia papilífera intraductal. Apesar do grande avanço nos métodos de avaliação por imagem pré-operatórios e mesmo com toda a expertise do cirurgião, os resultados mostram que o UIO modifica positivamente o planejamento cirúrgico em um número significativo de pacientes, devendo, portanto fazer parte integrante da avaliação intra-operatória dos pacientes candidatos à ressecção hepática por neoplasia primária ou secundária e da cirurgia de neoplasia endócrina pancreática / Intraoperative sonography (IOU) is an imaging modality that has been showing rapid growth in the last decade that can has a variety of applications in different surgical specialities, particularly in abdominal surgery. The purpose of this study was to analyze the use o IOU in the setting of surgery for liver, biliary and pancreatic malignancies. To achieve that, the findings of routine preoperative state-of the-art imaging modalities (CT and MRI) and the findings of surgical exploration (inspection and palpation) were compared to those of IOU. The impact of IOU on preoperative plans based on CT and MRI and on management after surgical exploration were studied as well 49 patients were retrospectively studied. Of those 15 had metastatic liver disease and 14 primary liver cancer; 14 had pancreatic neuroendocrine tumours and 6 had cystic pancreatic neoplasms. In the group of hepatic and biliary malignancies CT identified 65% of the tumours, surgical exploration identified 69.5% and IOU 95.2% (including 3 false positives). IOU determined a change in management in 34.4% of the patients. In the group of pancreatic neuroendocrine tumours the rates of identification were 27.3% for CT, 60.9% for MRI, 72.7% for surgical exploration and 100% for IOU, with an alteration in surgical plans in 42.9% of patients after IOU. In the case of patients with cystic pancreatic neoplasia, IOUS did not add any relevant additional information in relation to CT or MRI, with exception to one patient that had a papiliferous intraductal neoplasia. In spite of the great advances on preoperatory imaging modalities and of the possibility of direct surgical exploration, IOU has shown that it positively modifies surgical planning. For that reason, it should be included as an essential adjunct in the intraoperatory evaluation of patients with pancreatic endocrine neoplasia and of candidates for hepatic resection in cases of primary and secondary malignancies

Au cours de l'obésité, l'excès de lipides circulants, est stocké dans les organes périphériques, principalement dans le foie. Ce stockage ectopique de lipide peut avoir, à long terme, des conséquences délétères sur le métabolisme glucidique. Au long cours, l'excès de lipides hépatiques peut conduire au développement de stéatopathies métaboliques pouvant évoluer vers la cirrhose et le cancer du foie. Dans l'hépatocyte, le métabolisme et l'homéostasie lipidique sont finement régulés par la balance entre la synthèse (LDN) et l'utilisation (ß-oxydation) des lipides. Ces deux voies métaboliques sont sous le contrôle de plusieurs facteurs de transcriptions comme ChREBP, SREBP1 PPARƴ ou PPARa. La compaction et l'accessibilité de la chromatine sont des éléments cruciaux pour la régulation indirecte de l'activité de ces facteurs de transcription. Dans le noyau, la compaction de l'ADN est régulée par les histones mais aussi par les protéines High Mobility Group (HMG). Parmi la famille des protéines HMG, la protéine High Mobility Group box 1 (HMGB1), principalement localisée dans le noyau, est capable de réguler de façon indirecte la transcription de gènes dans de nombreux tissus. En plus de son rôle nucléaire, HMGB1 peut être activement sécrétée par les cellules innées au cours de phénomènes inflammatoires aigus. Chez la souris, la délétion totale de cette protéine entraine une hypoglycémie périnatale létale. De plus, chez la souris, les concentrations circulantes d'HMGB1 sont augmentées lors d'un stress métabolique induit par un régime hyper-lipidique (HFD). Tous ces résultats suggèrent un rôle d'HMGB1 dans le métabolisme hépatique et énergétique ainsi que dans les processus inflammatoires de bas-bruits associés au stress métabolique. [...] / During obesity, the excess of circulating lipids, are stored in the peripheral organs, and mainly in the liver. This ectopic storage of lipids may have long-term deleterious consequences on carbohydrate metabolism. Over time, excess of intra-hepatic lipids can lead to the development of steatohepatitis that can evolve to cirrhosis and liver cancer. In the hepatocyte, lipid homeostasis is finely regulated by the balance between synthesis (de novo lipogenesis-DNL) and degradation (ß-oxidation) of lipids. These two metabolic pathways are under the control of several transcription factors like ChREBP, SREBP1, PPARƴ or PPARa. The compaction and accessibility of chromatin are crucial parameters, which regulate the activity of these transcription factors. In the nucleus, the compaction of DNA is regulated by histones but also by High Mobility Group (HMG) proteins. Among the HMG protein family, High Mobility Group box 1 protein (HMGB1), mainly located in the nucleus, is able to indirectly regulate gene transcription in many tissues. In addition to its nuclear role, HMGB1 can be actively secreted by innate immunes cells during acute inflammatory reactions. In mice, the global deletion of Hmgb1 gene leads to perinatal lethality due to a severe hypoglycemia. Moreover, preliminary data from our laboratory show that circulating concentrations of HMGB1 are increased in mice subjected to high fat diet (HFD). All these results support a role of HMGB1 in hepatic and energetic metabolism but also in tissue-low grade inflammation related to metabolic stress. [...]

El MELD y el sodio sérico son factores pronósticos en la cirrosis, pero no queda claro su papel en la evaluación del pronóstico en lista de espera para trasplante hepático y en tras el mismo. El objetivo de la presente tesis doctoral es evaluar la utlidad del MELD y el sodio sérico en la valoración pronóstica del paicente cirrótico antes y después del trasplante hepático. En el primer estudio se incluyeron 308 pacientes en lista de espera para trasplante hepático durante un periodo de 5 años encontrando que el MELD y el sodio sérico fueron los únicos factores independientes de supervivencia a los 3 y 12 meses de la inclusión en lista de espera, pero la adición del sodio al MELD no mejoró su capacidad para predecir el pronóstico. En el segundo estudio se incluyeron 241 pacientes trasplantados durante un periodo de 3 años con el objetivo de evaluar el papel de la hiponatremia al momento del trasplante sobre el pronóstico post-trasplante hepático. En este estudio se encontró que los pacientes con hiponatremia al trasplante presentaron un mayor número de complicaciones neurológicas, infecciones e insuficiencia renal durante el primer mes post-trasplante hepático. Además la supervivencia a los 3 meses postrasplante fue significativamente más baja en los pacientes con hiponatremia. De los resultados de la presente tesis doctoral se puede concluir lo siguente: 1) En pacientes con cirrosis la presencia de hiponatremia se asocia con mayor número de complicaciones tras el trasplante hepático. 2) La presencia de hiponatremia pre-trasplante hepático se asocia con una menor supervivencia a los 3 meses post-trasplante hepático. 3) El MELD y el sodio son predictores independiente de supervivencia en lista de espera para trasplante hepático. 4) La adición del sodio sérico al MELD no mejoró su capacidad en la predicción de la supervivencia en lista de espera.

O objetivo do presente trabalho foi avaliar o valor diagnóstico e o impacto na modificação da conduta terapêutica do ultra-som intra-operatório (UIO) na cirurgia por neoplasia de fígado, vias biliares e pâncreas, comparando-se achados da avaliação pré-operatória de rotina com métodos de imagem convencionais (tomografia computadorizada e ressonância magnética) com achados obtidos por meio da exploração cirúrgica (inspeção e palpação). Foram analisados, retrospectivamente, exames realizados em 49 pacientes, sendo 15 portadores de neoplasia hepática secundária; 14, de neoplasia hepática primária; 14, de tumor neuroendócrino pancreático e seis de neoplasia cística pancreática. No grupo de pacientes com neoplasia hepática e de vias biliares, a TC identificou 65% dos tumores; a exploração cirúrgica, 69,5% e o UIO, 95,2%. Houve mudança da conduta, em decorrência dos achados do UIO, em 34,4% dos pacientes. No grupo de tumores neuroendócrinos pancreáticos, a TC identificou corretamente 44,4% dos tumores; a RM, 60,9%; a exploração cirúrgica com palpação, 72,7% e o UIO, 100%. Houve mudança de conduta em 42,9% dos pacientes. No grupo de neoplasia cística, o UIO não acrescentou informação adicional relevante em relação à TC e à RM, exceto no paciente com neoplasia papilífera intraductal. Apesar do grande avanço nos métodos de avaliação por imagem pré-operatórios e mesmo com toda a expertise do cirurgião, os resultados mostram que o UIO modifica positivamente o planejamento cirúrgico em um número significativo de pacientes, devendo, portanto fazer parte integrante da avaliação intra-operatória dos pacientes candidatos à ressecção hepática por neoplasia primária ou secundária e da cirurgia de neoplasia endócrina pancreática / Intraoperative sonography (IOU) is an imaging modality that has been showing rapid growth in the last decade that can has a variety of applications in different surgical specialities, particularly in abdominal surgery. The purpose of this study was to analyze the use o IOU in the setting of surgery for liver, biliary and pancreatic malignancies. To achieve that, the findings of routine preoperative state-of the-art imaging modalities (CT and MRI) and the findings of surgical exploration (inspection and palpation) were compared to those of IOU. The impact of IOU on preoperative plans based on CT and MRI and on management after surgical exploration were studied as well 49 patients were retrospectively studied. Of those 15 had metastatic liver disease and 14 primary liver cancer; 14 had pancreatic neuroendocrine tumours and 6 had cystic pancreatic neoplasms. In the group of hepatic and biliary malignancies CT identified 65% of the tumours, surgical exploration identified 69.5% and IOU 95.2% (including 3 false positives). IOU determined a change in management in 34.4% of the patients. In the group of pancreatic neuroendocrine tumours the rates of identification were 27.3% for CT, 60.9% for MRI, 72.7% for surgical exploration and 100% for IOU, with an alteration in surgical plans in 42.9% of patients after IOU. In the case of patients with cystic pancreatic neoplasia, IOUS did not add any relevant additional information in relation to CT or MRI, with exception to one patient that had a papiliferous intraductal neoplasia. In spite of the great advances on preoperatory imaging modalities and of the possibility of direct surgical exploration, IOU has shown that it positively modifies surgical planning. For that reason, it should be included as an essential adjunct in the intraoperatory evaluation of patients with pancreatic endocrine neoplasia and of candidates for hepatic resection in cases of primary and secondary malignancies

Transplantation of adult human hepatic stem/progenitor cells (hHSPCs) has been considered as an alternative therapy, replacing donor liver transplantation to treat liver cirrhosis. This study assessed the antifibrotic effects of hHSPCs in mice with fibrosis induced by carbon tetrachloride (CCl4) and examined the actions of hHSPCs on the fibrogenic activity of human hepatic stellate cells (HSCs) in a coculture system. Isolated hHSPCs expressed stem/progenitor cell phenotypic markers. Mice were given CCl4 (twice weekly for 7 weeks) and hHSPC transplantation weekly. CCl4 induced advanced fibrosis (bridging fibrosis and cirrhosis) in mice, which was prevented by hHSPC transplantation. The liver of hHSPC-transplanted mice showed only occasional short septa and focal parenchymal fibrosis, and a 50% reduction in hepatic collagen, assessed by Sirius red stain histomorphometry. Moreover, the proteins for α-smooth muscle actin (α-SMA) and collagen I were decreased. While α-SMA, collagen α1(I), and tissue inhibitor of metalloproproteinase-1 mRNAs were decreased, matrix metalloproteinase (MMP)-1 mRNA was increased, consistent with decreased fibrogenesis. MMP-2 and transforming growth factor-Β were not affected. Alanine aminotransferase and aspartate aminotransferase were lower, suggesting improvement of liver function/damage. In coculture, hHSPCs elicited changes of α-SMA and fibrogenic molecules in HSCs similar to those observed in vivo, providing evidence for a functional link between hHSPCs and HSCs. A decreased HSC proliferation was noted. Thus, transplantation of hHSPCs prevents histogenesis of advanced liver fibrosis caused by CCl4. hHSPCs mediate downregulation of HSC activation coincident with modulation of fibrogenic molecule expression, leading to suppression of fibrogenesis both in vivo and in vitro.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13449号 / 論医博第2242号 / 新制||医||1054(附属図書館) / 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 妹尾 浩, 教授 柳田 素子 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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