Publicação
Energy for Liver Regeneration: Mitochondrial Bioenergetics and the Pathogenesis of Posthepatectomy Liver Dysfunction
| Resumo: | Clinical success of hepatectomy relies on the liver’s unique capacity to regenerate, a highly energy-dependent process. When this capacity is surpassed Posthepatectomy Liver Failure (PHLF) ensues, resulting in increased morbidity and mortality. Mitochondria are the powerhouses of the eukaryote cell and decision-makers of cell death. Mitochondrial metabolism supplies the energy for liver regeneration, but the clinical consequences of mitochondrial dysfunction in posthepatectomy morbidity and liver function are presently unknown. Other unresolved issues are the effects of chemotherapy-associated liver injury (CALI) on outcome, as well as the possible contribution of bioenergetic dysfunction to the pathogenesis of CALI. Finally, two-stage hepatectomies rely on an extremely rapid and significant inter-stages regenerative response, but the energetic adaptations taking place in the future liver remnant (FLR) are largely unknown. Mitochondrial oxidative phosphorylation and respiration are key events in cellular energy metabolism and can be directly measured in liver biopsies. In this Doctoral Thesis the following objectives were pursued: 1) Review the role of energy metabolism in liver regeneration; 2) Determine whether changes in mitochondrial function correlate with clinical outcome in Humans undergoing hepatectomy; 3) Assess the impact of hepatic pedicle clamping (HPC) on intraoperative mitochondrial function; 4) Evaluate the impact of chemotherapy-induced hepatotoxicity on postoperative morbidity and the putative role of mitochondrial dysfunction in its pathogenesis; 5) Investigate the bioenergetics adaptations underlying the enhanced regenerative response taking place in two-stage hepatectomies. For the first objective, a non-systematic review of relevant published material in the English language was conducted. Reference lists were cross-checked for further relevant publications. Mitochondrial oxidative phosphorylation was summarily reviewed, as well as the role of mitochondria in both apoptotic and necrotic cell death. The key role of mitochondrial metabolism in the cellular events leading to liver regeneration was confirmed. For the second and third objectives, both experimental and clinical works were performed. First, a prospective study of patients undergoing hepatectomy for diverse indications (N=30) was conducted. Liver biopsies were performed in two distinct moments, at the beginning and at the end of surgery. Mitochondria were isolated and membrane potential and respiration were measured. Mitochondrial lag phase, reflecting the time required for adenosine diphosphate phosphorylation, presented high sensitivity and specificity for prediction of PHLF; a finding previously unreported in the scientific literature. Several key markers of postoperative liver function presented significant correlations with intraoperative fluctuations in mitochondrial membrane potential and respiration. An experimental study (N=35 male Wistar rats) was also outlined to explore the effect of 70% hepatectomy with HPC on energy metabolism, liver function and injury. In both studies, clinical and experimental, HPC was associated with depressed mitochondrial function. The fourth objective was addressed with two different methods. First, a clinical and pathologic review of 140 patients undergoing hepatectomy for colorectal cancer liver metastases was performed to look into the incidence, pathological spectrum and clinical consequences of CALI. Sinusoidal obstruction syndrome (SOS) was present in 52% of patients and independently associated with overall and liver-specific morbidity. Secondly, an experimental study (N=12 male Wistar rats), attempted to replicate a previously described animal model of SOS. Hepatectomy with HPC was performed to explore the possible link of mitochondrial dysfunction in the pathogenesis of posthepatectomy liver dysfunction in CALI. Although the characteristic histologic findings of SOS were not found, chemotherapy-treated animals presented evidence of disturbed hepatocellular bioenergetics, namely longer lag phase and increased mitochondrial size. Finally, another original prospective clinical study was conducted on patients undergoing the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) procedure (N=5). In this study, mitochondrial membrane potential and respiration were measured as well as gene expression profile. An inter-stages increase in energetic capacity was demonstrated in the FLR, as well as a strong and significant correlation of energy status with inter-stages volume growth. An increased expression of several genes associated with liver regeneration (Augmenter of Liver Regeneration; Small heterodimer partner; Signal Transducer and Activator of Transcription 3), mitochondrial biogenesis (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and energy metabolism (Cytochrome oxidase subunit I; Nicotinamide phosphoribosyltransferase) was also described. To our knowledge, this is the first ever documentation of adaptations in energy metabolism in two-stage hepatectomies in Humans. In conclusion, not only is Liver Regeneration highly dependent on energy metabolism, but also mitochondrial dysfunction was demonstrated to be involved in the pathogenesis of PHLF. The clinical relevance of mitochondrial bioenergetics in clinical liver resection deserves further exploration, with particular emphasis on the accurate perioperative staging of liver energy status as well as energy-conditioning therapies aiming at decreasing morbidity and mortality. |
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| Autores principais: | Alexandrino, Henrique Miguel Marques Bom Borges |
| Assunto: | Fígado Liver Hepatectomia Hepatectomy Mitocôndria Mitochondria Regeneração hepática Liver regeneration Insuficiência hepática Liver failure Bioenergética Bioenergetics |
| Ano: | 2017 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Coimbra |
| Idioma: | inglês |
| Origem: | Estudo Geral - Universidade de Coimbra |
| Resumo: | Clinical success of hepatectomy relies on the liver’s unique capacity to regenerate, a highly energy-dependent process. When this capacity is surpassed Posthepatectomy Liver Failure (PHLF) ensues, resulting in increased morbidity and mortality. Mitochondria are the powerhouses of the eukaryote cell and decision-makers of cell death. Mitochondrial metabolism supplies the energy for liver regeneration, but the clinical consequences of mitochondrial dysfunction in posthepatectomy morbidity and liver function are presently unknown. Other unresolved issues are the effects of chemotherapy-associated liver injury (CALI) on outcome, as well as the possible contribution of bioenergetic dysfunction to the pathogenesis of CALI. Finally, two-stage hepatectomies rely on an extremely rapid and significant inter-stages regenerative response, but the energetic adaptations taking place in the future liver remnant (FLR) are largely unknown. Mitochondrial oxidative phosphorylation and respiration are key events in cellular energy metabolism and can be directly measured in liver biopsies. In this Doctoral Thesis the following objectives were pursued: 1) Review the role of energy metabolism in liver regeneration; 2) Determine whether changes in mitochondrial function correlate with clinical outcome in Humans undergoing hepatectomy; 3) Assess the impact of hepatic pedicle clamping (HPC) on intraoperative mitochondrial function; 4) Evaluate the impact of chemotherapy-induced hepatotoxicity on postoperative morbidity and the putative role of mitochondrial dysfunction in its pathogenesis; 5) Investigate the bioenergetics adaptations underlying the enhanced regenerative response taking place in two-stage hepatectomies. For the first objective, a non-systematic review of relevant published material in the English language was conducted. Reference lists were cross-checked for further relevant publications. Mitochondrial oxidative phosphorylation was summarily reviewed, as well as the role of mitochondria in both apoptotic and necrotic cell death. The key role of mitochondrial metabolism in the cellular events leading to liver regeneration was confirmed. For the second and third objectives, both experimental and clinical works were performed. First, a prospective study of patients undergoing hepatectomy for diverse indications (N=30) was conducted. Liver biopsies were performed in two distinct moments, at the beginning and at the end of surgery. Mitochondria were isolated and membrane potential and respiration were measured. Mitochondrial lag phase, reflecting the time required for adenosine diphosphate phosphorylation, presented high sensitivity and specificity for prediction of PHLF; a finding previously unreported in the scientific literature. Several key markers of postoperative liver function presented significant correlations with intraoperative fluctuations in mitochondrial membrane potential and respiration. An experimental study (N=35 male Wistar rats) was also outlined to explore the effect of 70% hepatectomy with HPC on energy metabolism, liver function and injury. In both studies, clinical and experimental, HPC was associated with depressed mitochondrial function. The fourth objective was addressed with two different methods. First, a clinical and pathologic review of 140 patients undergoing hepatectomy for colorectal cancer liver metastases was performed to look into the incidence, pathological spectrum and clinical consequences of CALI. Sinusoidal obstruction syndrome (SOS) was present in 52% of patients and independently associated with overall and liver-specific morbidity. Secondly, an experimental study (N=12 male Wistar rats), attempted to replicate a previously described animal model of SOS. Hepatectomy with HPC was performed to explore the possible link of mitochondrial dysfunction in the pathogenesis of posthepatectomy liver dysfunction in CALI. Although the characteristic histologic findings of SOS were not found, chemotherapy-treated animals presented evidence of disturbed hepatocellular bioenergetics, namely longer lag phase and increased mitochondrial size. Finally, another original prospective clinical study was conducted on patients undergoing the Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy (ALPPS) procedure (N=5). In this study, mitochondrial membrane potential and respiration were measured as well as gene expression profile. An inter-stages increase in energetic capacity was demonstrated in the FLR, as well as a strong and significant correlation of energy status with inter-stages volume growth. An increased expression of several genes associated with liver regeneration (Augmenter of Liver Regeneration; Small heterodimer partner; Signal Transducer and Activator of Transcription 3), mitochondrial biogenesis (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha) and energy metabolism (Cytochrome oxidase subunit I; Nicotinamide phosphoribosyltransferase) was also described. To our knowledge, this is the first ever documentation of adaptations in energy metabolism in two-stage hepatectomies in Humans. In conclusion, not only is Liver Regeneration highly dependent on energy metabolism, but also mitochondrial dysfunction was demonstrated to be involved in the pathogenesis of PHLF. The clinical relevance of mitochondrial bioenergetics in clinical liver resection deserves further exploration, with particular emphasis on the accurate perioperative staging of liver energy status as well as energy-conditioning therapies aiming at decreasing morbidity and mortality. |
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Atividades financiadas
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