La bronchopneumopathie chronique obstructive (BPCO) est une des maladies chroniques les plus fréquentes et constitue une des premières causes de mortalité dans le monde avec un impact sociétal majeur et des couts de santé considérables. La BPCO est aujourd’hui considérée comme une maladie multi-systémique dont le pronostic est lié en grande partie à ses comorbidités et à la survenue d’exacerbations. Les exacerbations qui vont ponctuer l’évolution de la BPCO précipitent le déclin de la fonction respiratoire et favorisent la décompensation des comorbidités et la survenue d’événements cardiovasculaires comme des infarctus du myocarde ou des accidents vasculaires cérébraux. La prise en charge moderne de la BPCO est basée sur la mise en place d’un soin intégré incluant la prise en charge des comorbidités et une meilleure détection et gestion des exacerbations.Dans ce travail de thèse nous abordons l’atteinte hépatique (stéatopathie hépatique non alcoolique - NAFLD) dans la BPCO comme une comorbidité sous-estimée (publication 1) alors qu’elle a probablement des implications pronostiques importantes (publication 2). La BPCO s'accompagne également de symptômes non respiratoires tel que des douleurs, dont les variations et localisations sont peu connues pendant et après l'exacerbation (publication 3). Le traitement de ces douleurs par des opiacés pourrait avoir un effet spécifiquement délétère dans cette population (publication 5). Les enjeux de réforme du système de santé avec une optimisation cout-efficacité incitent à développer et valider de nouvelles méthodes de prise en charge ambulatoire des exacerbations (publication 6).Dans une première partie de la thèse nous explorons les liens épidémiologiques entre BPCO et NAFLD. Nous explorerons également les conséquences d’une telle association sur le devenir cardiovasculaire des patients à moyen terme. Dans une deuxième partie, nous cherchons à définir les caractéristiques des douleurs avant et après exacerbation au cours de la BPCO, le lien entre douleur, anxiété et dépression chez ces patients et la sécurité d'emploi des morphiniques dans cette population fragile. Dans une dernière partie, nous aborderons la stratification du risque lié à une exacerbation de BPCO, et la possibilité d’une prise en charge ambulatoire extrahospitalière pour les exacerbations de sévérité modérée. / Chronic Obstructive Pulmonary Disease (COPD) is one of the most common chronic diseases and is one of the leading causes of death in the world with major societal impact and considerable health costs. COPD is now considered a multi-systemic disease whose prognosis is largely related to its comorbidities and the occurrence of exacerbations. The exacerbations that punctuate the evolution of COPD precipitate the decline of respiratory function and promote the decompensation of comorbidities and the occurrence of cardiovascular events such as myocardial infarction or cerebrovascular accidents. The modern management of COPD is based on the implementation of integrated care including the management of comorbidities and better detection and management of exacerbations.In this thesis we address liver injury (non-alcoholic fatty liver disease - NAFLD) in COPD as an underestimated comorbidity (publication 1), although it probably has important prognostic implications (publication 2). COPD is also associated with non-respiratory symptoms such as pain, the variations and locations of which are poorly known during and after exacerbation (publication 3). Treatment of this pain with opiates may have a specifically deleterious effect in this population (publication 5). The challenges of health system reform with cost-effectiveness optimization encourage the development and validation of new methods of outpatient management of exacerbations (publication 6).In a first part of the thesis we explore the epidemiological links between COPD and NAFLD. We will also explore the consequences of such an association on the cardiovascular outcome of patients in the medium term. In a second part, we seek to define the characteristics of pain before and after exacerbation during COPD, the link between pain, anxiety and depression in these patients and the safety of opioids in this fragile population. In the last part, we will discuss the stratification of the risk linked to an exacerbation of COPD, and the possibility of outpatient care for exacerbations of moderate severity.

Alcohol-related Liver Disease (ALD) represents almost half of all deaths attributable to liver disease (LD) in the US. Despite the large proportion of deaths from ALD, however, only 1.4% of all liver transplants were for patients with ALD. ALD presents a range of medical and ethical concerns for those who drive the policy and practices of liver transplantation (LT). While, historically, stringent eligibility criteria for LT precluded many with ALD from receiving a transplant, more recent research suggests such criteria may be misguided. The following review compares LT outcomes between ALD and non-ALD recipients and finds that LT recipients with ALD have equal, if not better, survival rates than those with non-ALD. The findings of this review suggest a need for revisiting transplant criteria for patients with ALD to ensure parity.

Introduction: Non-invasive assessment of steatosis and fibrosis is of growing relevance in non-alcoholic fatty liver disease (NAFLD). 1H-Magnetic resonance spectroscopy (1H-MRS) and the ultrasound-based controlled attenuation parameter (CAP) correlate with biopsy proven steatosis, but have not been correlated with each other so far. We therefore performed a headto- head comparison between both methods. Methods: Fifty patients with biopsy-proven NAFLD and 15 healthy volunteers were evaluated with 1H-MRS and transient elastography (TE) including CAP. Steatosis was defined according to the percentage of affected hepatocytes: S1 5-33%, S2 34–66%, S3 $67%. Results: Steatosis grade in patients with NAFLD was S1 36%, S2 40% and S3 24%. CAP and 1H-MRS significantly correlated with histopathology and showed comparable accuracy for the detection of hepatic steatosis: areas under the receiveroperating characteristics curves were 0.93 vs. 0.88 for steatosis $S1 and 0.94 vs. 0.88 for $S2, respectively. Boot-strapping analysis revealed a CAP cut-off of 300 dB/m for detection of S2-3 steatosis, while retaining the lower cut-off of 215 dB/m for the definition of healthy individuals. Direct comparison between CAP and 1H-MRS revealed only modest correlation (total cohort: r = 0.63 [0.44, 0.76]; NAFLD cases: r = 0.56 [0.32, 0.74]). For detection of F2–4 fibrosis TE had sensitivity and specificity of 100% and 98.1% at a cut-off value of 8.85 kPa. Conclusion: Our data suggest a comparable diagnostic value of CAP and 1H-MRS for hepatic steatosis quantification. Combined with the simultaneous TE fibrosis assessment, CAP represents an efficient method for non-invasive characterization of NAFLD. Limited correlation between CAP and 1H-MRS may be explained by different technical aspects, anthropometry, and presence of advanced liver fibrosis.

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.

Non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent issue in the modern world, predisposing patients to serious pathology such as cirrhosis and hepatocellular carcinoma. Mitochondrial dysfunction, and in particular, diminished hepatic oxidative phosphorylation (OXPHOS) capacity, have been observed in NAFLD livers, which may participate in NAFLD pathogenesis. To examine the role of OXPHOS in NAFLD, we generated a model of enhanced hepatic OXPHOS using mice with liver-specific transgenic expression of LRPPRC, a protein which activates mitochondrial transcription and augments OXPHOS capacity. When challenged with high-fat feeding, mice with enhanced hepatic OXPHOS were protected from the development of liver steatosis and inflammation, critical components in the pathogenesis of NAFLD. This protection corresponded to increased liver and whole-body insulin sensitivity. Moreover, mice with enhanced hepatic OXPHOS have increased availability of oxidized NAD+, which promotes complete fatty acid oxidation in hepatocytes. Interestingly, mice with enhanced hepatic OXPHOS were also protected from obesogenic effects of long-term high-fat feeding. Consistent with this, enhanced hepatic OXPHOS increased energy expenditure and adipose tissue oxidative gene expression, suggesting a communication between the liver and adipose tissue to promote thermogenesis. Examination of pro-thermogenic molecules revealed altered bile acid composition in livers and serum of LRPPRC transgenic mice. These mice had increased expression of bile acid synthetic enzymes, genes which are induced by NAD+ dependent deacetylase SIRT1 activation of the transcriptional co-regulator PGC-1a. These findings suggest that enhanced hepatic OXPHOS transcriptionally regulates bile acid synthesis and dictates whole-body energy expenditure, culminating in protection from obesity.

Indiana University-Purdue University Indianapolis (IUPUI) / This thesis explores a minimally invasive approach of diagnosing Non-Alcoholic Fatty Liver disease (NAFLD) on mice and humans which can be useful for pathologists while performing their diagnosis. NAFLD is a spectrum of diseases going from least severe to most severe – steatosis, steatohepatitis, fibrosis and finally cirrhosis. This disease primarily results from fat deposition in the liver which is unrelated to alcohol or viral causes. In general, it affects individuals having a combination of at least three of the five metabolic syndromes namely, obesity, hypertension, diabetes, hypertriglyceridemia, and hyperlipidemia. Given how common these metabolic syndromes have become, the rate of NAFLD has increased dramatically over the years affecting about three-quarters of all obese individuals including many children, making it one of the most common diseases in United States. Our study focuses on building various computational models which help identify different histological features in a liver biopsy image, thereby analyzing if a person is affected by NAFLD or not. Here, we develop and validate the performance of automated classifiers built using image processing and machine learning methods for detection of macro- and microsteatosis, lobular and portal inflammation and also categorize different types fibrosis in murine and human fatty liver disease and study the correlation of automated quantification of macrosteatosis, lobular and portal inflammation, and fibrosis (amount of collagen) with expert pathologist’s semi-quantitative grades. Our research for macrosteatosis and microsteatosis prediction shows the model’s precision and sensitivity as 94.2%, 95% for macrosteatosis and 79.2%, 77% for microsteatosis. Our models detect lobular and portal inflammation(s) with a precision, sensitivity of 79.6%, 77.1% for lobular inflammation and 86%, 90.4% for portal inflammation. We also present the first study on identification of the six different types of fibrosis having a precision of 85.6% for normal fibrosis and >70% for portal fibrosis, periportal fibrosis, pericellular fibrosis, bridging fibrosis and cirrhosis. We have also quantified the amount of collagen in a liver biopsy and compared it to the pathologist semi-quantitative fibrosis grade.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21617号 / 医博第4423号 / 新制||医||1033(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 羽賀 博典, 教授 川口 義弥, 教授 妹尾 浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Background: It has been hypothesized that dysbiosis plays a significant role in the pathogenesis of intestinal failure–associated liver disease (IFALD). Therefore, we aimed to investigate the effect of probiotics on IFALD in patients receiving parenteral support, namely home parenteral nutrition (HPN) and home intravenous fluids (HIVFs). Methods: We retrospectively reviewed charts of patients with intestinal failure who received HPN or HIVF for >2 weeks at our tertiary center between January 2005 and August 2016. We excluded patients <18 years of age, patients with other causes of liver disease, patients who used probiotics for <30 days, patients with <6 months' follow-up, and those who had long-term antibiotic use (>30 days). Bivariable and multivariable logistic regression analyses were used in this study. Results: A total of 282 patients who received parenteral support were included. Eighty-five percent of our sample received PN. A total of 78 (27.7%) patients used probiotics. The prevalence of IFALD in patients who used probiotics was 35.9% vs 54.4% in patients who did not use probiotics, P =.005. In multivariable analysis, only small-bowel length of 10-90 cm and HPN use showed a significant impact on IFALD, odds ratio (OR) = 4.394 (95% confidence interval [CI], 1.635-11.814; P =.003) and OR = 4.502 (95% CI 1.412-14.351; P =.011), respectively. Conclusion: Our study revealed that the prevalence of IFALD was comparable among the probiotic users and nonusers. Only small bowel length of 1090 cm and HPN use showed a significant impact on IFALD.