Auswahl der wissenschaftlichen Literatur zum Thema „Metabolická chirurgie“

ZusammenfassungMan spricht heute von der Chirurgie der Adipositas und Adipositas-assoziierten Erkrankungen, denn die Adipositaschirurgie geht nicht nur mit einem Gewichtsverlust, sondern mit einer allen medikamentösen und konservativen Therapien weit überlegenen Verbesserung der Adipositas-assoziierten Erkrankungen einher. Aus diesem Grund wurde von der International Federation for the Surgery of Obesity and Metabolic Disorders (IFSO) ein aktualisiertes Position-Statement im August 2016 veröffentlicht. Dieses berücksichtigt die spezifischen Adipositas-assoziierten Erkrankungen und bezieht diese bei der Indikationsstellung zur Operation mit ein. Anhand der aktuellen Literatur werden Adipositas-assoziierte Erkrankungen diskutiert und evidenzbasierte Empfehlungen erstellt.

Molti lavori recenti analizzano l'associazione fra calcolosi renale e altre patologie non trasmissibili tipiche dei paesi industrializzati. I dati epidemiologici, su casistiche ampie, indicano un aumento di incidenza della calcolosi in pazienti con sindrome metabolica, obesità e ipertensione. Viene anche descritto un aumento del rischio di infarto miocardico e di ictus nei litiasici. Si ipotizza che il denominatore comune in queste patologie sia l'aumento della resistenza all'insulina. Questo causa alterazioni della biochimica urinaria, pH più acido e riduzione della citraturia, tali da aumentare il rischio litogeno. Nel ratto diabetico è stata descritta una steatosi renale che riduce l'ammoniogenesi e che è reversibile con una terapia con PPARγ. Il pioglitazone è stato efficace nel ridurre il danno renale indotto nel ratto da etilen glicole. Altra associazione nota è quella fra calcolosi renale e gotta. Due recenti studi documentano un'incidenza della calcolosi calcica e non solo urica nella gotta, con anomalie metaboliche in parte simili a quelle dei pazienti non gottosi. L'indagine TC mostra che l'incidenza di calcolosi è sottostimata nella gotta e, inoltre, la calcolosi, in alcuni pazienti, precede anche di molti anni l'attacco gottoso. Un altro argomento analizza il potenziale effetto che favorisce la calcolosi nelle donne trattate con calcio e vitamina D. Emergono un modesto ma significativo aumento del rischio litogeno indipendente da altre covariabili e un conseguente invito all'attenta valutazione del rapporto rischio/beneficio. La chirurgia bariatrica per la correzione della grave obesità era, in passato, gravata da un elevato rischio di calcolosi renale iperossalurica con quadri anche di ossalosi severa. Negli ultimi anni si sono diffuse tecniche meno litogene come il bendaggio gastrico e il bypass gastrico alla Roux. Iperossaluria e ipocitraturia conseguono a questi interventi e il rischio di calcolosi è di gran lunga inferiore, ma restano segnalazioni in letteratura di casi di ossalosi renale specialmente dopo bypass gastrico alla Roux.

Abstract Background: Primary thyroid lymphoma (PTL) is a rare condition representing <5% of thyroid malignancies with diffuse large B-cell lymphoma (DLBCL) as the most common subtype (1). Although not commonly managed in the endocrine sphere, identification is paramount to prognosis and treatment. We present a case of PTL to highlight the importance of diagnostic scrutiny and clinical follow up. Clinical Case: A 69-year-old man with a history of Hashimoto’s thyroiditis presented with an enlarging neck mass. The patient noted development of a left-sided anterior neck mass 3 days prior to seeking care. He denied compressive symptoms and B symptoms (weight loss, fevers, and night sweats). Physical exam revealed a large, firm left-sided thyroid nodule. Serum studies were notable for TSH 39.1 mcIU/mL (0.30-4.7 mcIU/mL), FT4 0.9 ng/dL (0.80-1.70 ng/dL), and TPO Ab 127 IU/mL (<=20 IU/mL). Levothyroxine 100 mcg daily was started. Neck ultrasonography showed a 54 mm hypoechoic, solid left thyroid nodule without calcifications. No abnormal cervical lymph nodes were present. FNA revealed a mixed population of small lymphocytes with no monoclonal B cell population or T cell aberrancies on flow cytometry. In the setting of ongoing nodular growth, the patient underwent core needle biopsy which revealed DLBCL (Ki67 proliferation index >80%, EBV-EBER negative). For diagnostic confirmation and staging, a whole-body FDG-PET scan was performed with an intensely FDG-avid left thyroid mass and no metabolic evidence of additional lymphoproliferative disease. Bone marrow biopsy did not show lymphomatous involvement. The patient was diagnosed with primary thyroid lymphoma and started on chemotherapy with R-CHOP. Conclusion: PTL commonly presents as a rapidly enlarging, painless neck mass that may be accompanied by B symptoms. Hashimoto’s thyroiditis is a known risk factor. Our case in particular required more diligence in the setting of an FNA with mixed lymphoid cells and negative flow cytometry. Initial differential diagnosis included intrathyroidal lymph node, Hashimoto’s thyroiditis, thyroid adenoma/malignancy with a false FNA, and lymphoma. Notably, FNA biopsy is only associated with 71% sensitivity in diagnosing PTL, whereas core biopsy has a 93% sensitivity rate (2). Upon histopathologic disease diagnosis, collaboration with oncology is needed for further staging and initiation of chemotherapy +/- radiation. References: (1) Pavlidis ET, Pavlidis TE. A Review of Primary Thyroid Lymphoma: Molecular Factors, Diagnosis and Management. J Invest Surg. 2019;32(2):137-142. (2) Diaconescu MR, Costea I, Glod M, Diaconescu S. An Unwonted Clinicopathological Subtype of Thyroid Primary Lymphoma. Chirurgia. 2016;111(5):428-431.

Les données de la littérature rapportent la supériorité de la chirurgie bariatrique sur le traitement médical optimisé concernant la perte pondérale et l'amélioration du diabète de type 2. Les facteurs prédictifs de bons résultats en terme pondéral et métabolique restent encore méconnus et des échecs sont constatés. Le phénotypage de l'obésité et de son retentissement métabolique semble essentiel afin d'adapter la procédure chirurgicale au cas par cas et améliorer les résultats. Dans ce travail de thèse, par une approche clinique, nous avons cherché à identifier les facteurs prédictifs d'amélioration des paramètres métaboliques et de succès pondéral après chirurgie bariatrique. Nous avons démontré le rôle majeur de la perte de poids après chirurgie dans l'amélioration du métabolisme glucidique et des paramètres métaboliques. Nous avons également montré l'impact positif de la masse musculaire initiale sur la perte pondérale, facteur également déterminant dans le contrôle du métabolisme glucidique. Les marqueurs du dysfonctionnement cellulaire Beta sont également apparus déterminants pour prédire la rémission du diabète de type 2 après chirurgie. Ainsi, l'efficacité de la chirurgie dans le contrôle du syndrome métabolique, au-delà de la technique opératoire, apparaît très dépendante de la perte de poids mais aussi du terrain, confirmant l'importance du phénotypage de l'obésité en préopératoire. Par une approche expérimentale, nous avons cherché à identifier l'impact du tissu adipeux sur les organes sièges de l'insulino-résistance (muscle et foie) impliqués dans le syndrome métabolique. La constitution de la tissuthèque DioMede et l'obtention de milieux conditionnés de tissu adipeux nous ont permis d'étudier l'impact des sécrétions de ce tissu sur les tissus insulino-sensibles en se rapprochant des conditions physiologiques. Nous avons identifié un effet direct du tissu adipeux sur le métabolisme musculaire des acides gras (AG) par la régulation négative du facteur de transcription SREBP-1c. Nos résultats identifient les acides gras insaturés comme les médiateurs de l'inhibition de SREBP-1, conduisant à une diminution de la lipogenèse par l'intermédiaire des gènes cibles de ce facteur de transcription. La composition et les proportions respectives d'AG mono ou poly insaturés et d'AG saturés dans le tissu adipeux, leur niveau de sécrétion, et leur taux circulant apparaissent donc déterminants dans la régulation de la lipogenèse des tissus insulino-sensibles (foie et muscle), et pourraient être un marqueur des obésités avec désordres métaboliques
Literature data reported the superiority of bariatric surgery on optimized medical treatment concerning weight loss outcomes and improvement of type 2 diabetes. Predictive factors of good weight loss results and metabolic control are still unrecognized and failures are recorded. Phenotyping obesity and its metabolic consequences seem essential to tailor the surgical procedure to each patient and to improve the outcomes. In this work, by a clinical approach, we have tried to identify predictive factors of metabolic control and weight loss after bariatric surgery. We have demonstrated the major role of weight loss to achieve glucose homeostasis and metabolic control. We have also reported the positive impact of initial Fat Free Mass on weight loss outcomes and glucose metabolism control. Beta cell dysfunction markers appeared to also have a major impact on Type 2 Diabetes remission after surgery. Thus, the efficacy of surgery on metabolic control, beyond the surgical technique, seems highly related to weight loss and patients history, which underlines the importance of phenotyping obesity before surgery. By an experimental approach, we have tried to identify the impact of adipose tissue on muscle and liver, organs that are involved in the metabolic syndrome. By means of a tissue collection (Diomede) and the use of conditioned media of adipose tissue, we studied the impact of adipose tissue secretions on insulin sensitive tissues, close to physiological conditions. We found a direct effect of adipose tissue on fatty acid metabolism in muscle through SREBP-1c down regulation. Unsaturated Fatty Acids were identified as the mediators of SREBP-1 inhibition, leading to a decrease in lipogenesis through target genes of this transcriptional factor. The composition and the respective proportion of mono or poly unsaturated fatty acids and saturated fatty acids in adipose tissue, their level of secretion, and their circulation rate appear to be determinant in lipogenesis regulation in insuline sensitive tissues (muscle and liver), and could be markers of metabolic disorders in obese patients

En plus de leur rôle dans la solubilisation des lipides alimentaires, les acides biliaires sont des molécules de signalisation régulant leur propre métabolisme, l'homéostasie du glucose et des lipides, la dépense énergétique, la fonction cardiovasculaire et l’inflammation, en modulant le Farnesoid X Receptor (FXR) et le Takeda G protein coupled Receptor 5 (TGR5). En effet, des modifications dans les concentrations des acides biliaires sont associées aux maladies métaboliques et ce sont des candidats pour participer à la pathophysiologie de ces maladies ou prédire leur progression.Dans la première partie de cette thèse nous avons étudié les modifications des acides biliaires dans le contexte de l'obésité, l'insulinorésistance, le diabète de type 2 et la stéatohépatite non alcoolique. Nous avons montré que les acides biliaires sont corrélés avec l’homéostasie du glucose chez l’Homme, mais qu’ils ne sont pas des prédicteurs de la bascule du prédiabète en diabète de type 2 dans un étude de cohorte.La deuxième partie de cette thèse est dédiée à l’étude des acides biliaires dans la chirurgie bariatrique. Nos résultats ont montré que la chirurgie bariatrique réduit la recapture hépatique des acides biliaires, provoquant leur augmentation dans la circulation systémique, et que ce n’est pas l’anse biliaire mais l’anse commune qui est responsable des modifications métaboliques après la chirurgie bariatrique chez le minipig. Ensuite, nous avons montré chez l’Homme que les acides biliaires liés aux lipoprotéines de haute densité (HDL) augmentent après la chirurgie bariatrique, et que cette augmentation est corrélée avec la restauration de leurs fonctions vaso-protectrices
In addition to their role in the solubilization of dietary lipids, bile acids are signaling molecules regulating their own metabolism, glucose and lipid homeostasis, energy expenditure, cardiovascular function and inflammation via the activation of the Farnesoid X Receptor (FXR) and the Takeda G protein coupled Receptor 5 (TGR5). Indeed, changes in bile acid concentrations are associated with metabolic diseases and therefore they are candidates to participate in the pathophysiology of these diseases or predict their progression.In the first part of this thesis, we studied bile acid changes in the context of obesity, insulin resistance, type 2 diabetes and non-alcoholic steatohepatitis. We demonstrated that bile acids are correlated with glucose homeostasis in humans, but that they are not predictors for the progression from prediabetes to type 2 diabetes in a longitudinal cohort study.In the second part of this thesis, we studied the bile acids in the context of bariatric surgery. Our results showed that bariatric surgery reduces the hepatic recapture of certain bile acids, causing them to increase in the systemic circulation. Additionally, we showed that it is not the bile limb but the common limb the one responsible for metabolic changes after bariatric surgery in the minipig. Finally, we showed in humans that bile acids linked to high-density lipoproteins (HDL) increase after bariatric surgery, and that this increase is correlated with the restoration of their vasoprotective functions

Le pregnane X receptor (PXR) est un récepteur nucléaire associé à la réponse au stresscellulaire. Des travaux in vitro de notre groupe ont démontré que les activateurs de cerécepteur (spironolactone (SPIR), clotrimazole (CTZ)) inhibent significativement l’apoptosespontanée ou induite, dans des primo-cultures d’hépatocytes de rat ou d’origine humaine.Les données in vitro sont en faveur d’un rôle clé du PXR dans la protection hépatique contreles xénobiotiques et endobiotiques en régulant de façon concertée leur détoxication(transport, métabolisme) et en augmentant leur résistance à l’apoptose. D’autres travauxrécents ont démontré le rôle majeur de ce récepteur dans la régulation de l’homéostasielipidique et glucidique, d’une part en favorisant la lipogenèse, d’autre part inhibant la lipolyseet la néoglucogenèse. L’induction du PXR peut être responsable de l’accumulation de lipidesdans le foie (NAFLD non alcoholic fatty liver disease). La NAFLD est fortement associée àl’obésité. La chirurgie bariatrique est à ce jour le seul traitement efficace à long terme pourl’obésité morbide. L’évolution des lésions hépatiques de la NAFLD après chirurgiebariatrique n’est pas complètement élucidée. L’objectif de ce travail de thèse, a été d’analyser si, in vivo, les agonistes du PXR tels que le CTZ et la SPIR, présentaient chez l’animal les mêmes effets que ceux décrits in vitro, et s’ilspouvaient conduire à une protection similaire du foie, lors d’atteintes pathologiques commeles lésions hépatiques induites par l’ischémie reperfusion. Dans un autre chapitre les effetsde deux procédures bariatriques, le court circuit gastrique (gastric bypass- GBP) et lagastrectomie en gouttière (sleeve gastrectomy- SG), sur le comorbiditées liées à la obésitéont été analysés. Le modèle d’ischémie reperfusion normothermique partielle et totale du foie chez le rongeur(rat et souris) a été utilisé pour étudier le rôle protecteur du PXR contre les lésionsapoptotiques. Les effets du court circuit gastrique sur les comorbiditées associées à l’obésitéont été étudiés dans deux groupes de patients obèses (index de masse corporelle > 50Kg/m2 et < 50 Kg/m2). Les résultats du GBP et de la SG ont été étudiés dans deux groupescomparables de sujets super obèses (IMC > 50 Kg/m2).Résultats 1/ Le traitement par les activateurs du PXR (CTZ et SPIR), chez le rat et chezla souris, provoque l’induction d’expression du CYP 3A1, enzyme sous le contrôle du PXR. Ilest associé à une réduction significative du nombre d’hépatocytes apoptotiques, du niveaudes transaminases, de la caspases activée et de son substrat PARP (poly-ADP-ribosepolymérase).Les mécanismes impliqués comprennent l’induction d’expression de la protéineantiapoptotique Bcl-xL, l’activation de la voie MAP kinase ERK ½, l’inhibition de l’activationde JNK et la sous-expression des heat schock proteins 27, 70, et 90, dans le cas del’ischémie complète du foie. 2/ Un an après l’intervention bariatique, le GBP a montré uneefficacité comparable sur la réversibilité du syndrome métabolique, de l’inflammationsystémique et l’insulino résistance chez les femmes super-obèses et obèses morbides,même si l’IMC moyen des patientes super obèses est resté significativement plus élevé. LeGBP et la SG conduisent à des résultats comparables, 6 mois après la chirurgie, mais lepremier est significativement plus efficace en termes d’amélioration du profil lipidique,d’inflammation à bas grade et de syndrome métabolique.L’activation du PXR est associée à un effet de protection hépatique contre les lésionsd’ischémie reperfusion. Le GBP est efficace sur les comorbiditées chez le super obèseautant que chez l’obèse morbide. ll donne également de meilleurs résultats à un an, sur laperte de poids, l’inflammation systémique et la régression du syndrome métabolique
The pregnane X receptor (PXR) is a nuclear receptor associated with cellularresponse to xeno and endobiotics. Recently, the involvement of PXR in controlling otherfunctions has been clarified. We previously showed in our laboratory that the PXR activators(spironolactone (SPIR) and clotrimazole (CTZ) protect primoculture of human or rathépatocytes against apoptosis. In vitro data are indicate that the PXR plays a major role inthe protection of the liver against xeno and endobiotics trough the régulation of theirélimination (détoxication) and increasing their resistance against apoptosis. It has also beenshown that the PXR is implicated in the controls of lipid and carbohydrates metabolism. Theinduction of PXR increases lipogenesis, inhibits lipolysis and neoglucogenesis. PXRinduction may be responsible for the accumulations of lipids into the liver (NAFLD, nonalcoholic liver disease). This disease is strongly associated with obesity. To date bariatricsurgery is only effective treatment in the long term for morbid obesity. The evolution ofNAFLD following bariatric surgery has not been fully clarified.Aims The aims of this thesis were to ascertain whether PXR agonists such as CTZ andSPIR resulted in the same effects in the animal model than those observed in vitro andwhether the administration of these drugs was associated with any protection againstnormothermic ischemia reperfusion injury of the liver. In another chapter the effects onobesity related comorbidities of two bariatric procedures such as the gastric bypass and thesleeve gastrectomy were investigated. The animal model used to investigate the role of PXR against apoptosis wasthe partial and total normothermic ischemia reperfusion of the liver in the rodent (rat andmouse). The effects of the GBP and SG on obesity related comorbidities wereinvestigated in two groups of obese women (BMI > 50 Kg/m2 and < 50kg/m2). The results ofGBP and SG in two comparable groups of super obese patients (BMI > 50 Kg/m2) wereinvestigated. Treatment with PXR activators such as (CTZ and SPIR) in the rat and in themouse was associated with the induction of CYP 3A1, an enzyme directly controlled by thePXR, with a significant reduction of the apoptotic hepatocytes, with a significantly lowerlevels of transaminases, activated caspase 3 and its substrate PARP (poly-ADP-ribosepolymérase).The involved mécanismes include the induction of the expression of theantiapoptotic protein Bcl-xL, the activation of the extracellular regulated kinase (ERK ½), theinhibition of JNK and the down régulation of heat shock proteins (hsp 27, 70, and 90) geneexpression in the case of total liver ischemia. One year after surgery GBP showedcomparable results in terms of résolution of metabolic syndrome, systemic inflammation andinsuline resistance in morbdly obese as well as super obese women even if the mean BMI ofsuper obese women remained higher (34.7 Kg/m2 vs 28.1 Kg/m2). GBP and SG areassociated with the same results six months after surgery but GBP is more effective inimproving lipid disturbances, low-grade systemic inflammation and the metabolic syndromeat one year. PXR induction results in a protective effect against normothermic inschemiareperfusion injury in the rodent. Results of GBP in terms of resolution of obesity relatedcomorbidities are comparable in the super obese and morbidly patients. GBP is moreeffective than SG one year after surgery in terms of weight loss, and resolution of lipiddisturbances, low-grade systemic inflammation and metabolic syndrome

Introduction: Bariatric metabolic surgery is recognized as a very effective treatment for obesity, performed when the preceding conventional treatment failed or when significant obesity-related complications occured. Diploma thesis is focused on a current practice of dietitians providing nutritional care in weight-loss surgery (WLS), as they play an important role in a multidisciplinary medical team by performing a clinical nutritional evaluation, education and long-term nutritional follow-up. Objective: The aim of the thesis is to present eating habits in patients of the 3rd Medical Department of the 1st Faculty of Medicine Charles University and General Faculty Hospital in Prague, in 6 and 12 months after the surgery and to evaluate its accordance to existing nutritional strategies and evidence-base guidelines. Methods: A cross-sectional observational study is focused on nutritional assessment and therapy in management of obesity in 13 patients 6 months post-WLS (M6: 31 % female, 69 % male; mean age 49 ± 8,56 years; mean body weight 119,3 ± 16,64 kg; mean BMI 39,7 ± 6,05 kg/m2 ) and in 17 patients 12 months post-WLS (Y1: 71 % female, 29 % male; age 53 ± 8,01 years; body weight 114,9 ± 31,72 kg; BMI 39,3 ± 6,75 kg/m2 ) together with a control group without surgery (age 47 ± 15 years; body weigh...

This thesis focuse on bariatric-metabolic surgery and its impact on serum concentrations of various metabolic parameters. The thesis is divided into two parts - theoretical and practical. Basic facts about bariatric-metabolic surgery such as its history, indications, contraindications, surgical methods and their results, nutrition after surgery and the frequency of micronutrient's deficits are described in the theoretical part. Furthermore, information about calcium-phosphate metabolism and metabolites such as calcium, phosphorus, magnesium, vitamin D, vitamin K, parathyroid hormone and osteomarkers is also included. The influence of nutrition and nutritional status on the quality of bone tissue is also mentioned. Last section of the theoretical part is focused on the important vitamins and minerals. The practical part discusses measurements of selected metabolites in serum before and half a year after the surgery. Results of questionnaires which were given to respondents are also included. Questionnaires were focused on lifestyle, nutrition, physical activities and whether the patients take some supplements of micronutrients and protein concentrates. The goal of this work is to evaluate the effect of the surgery on serum concentrations of metabolic parameters and their effect on the health and...

The diploma thesis deals the problematics of weight reduction with the using of bariatric- metabolic surgery and focuses on the changing risk components of the metabolic syndrome during one year long observation of 45 probands who have undergone Partial Jejuno-Ileal Diversion, Laparoscopic Sleeve Gastrectomy or Laparoscopic Gastric Plication. The main aim of the diploma thesis is to evaluate the changing risk components of the metabolic syndrome during weight reduction after undergoing bariatric surgery. The thesis shows that in the studied sample of bariatric patients it is an effective method of weight reduction (in PJID the success rate was 48 % EWL, in LGCP 51 % EWL and the most successful was LSG with 76 % EWL) with metabolic effect such as for example observed positive changes in risk components of the metabolic syndrome - reduction of morning glucose levels, increase of HDL cholesterol and decrease of triacylglycerols in the blood, decrease of waist circumferences and decrease of blood pressure or elimination of metabolic syndrome. Up to 68.9 % of the monitored probands showed signs of metabolic syndrome when evaluating the initial measurement before bariatric surgery, the remaining 22.2 % of the probands showed the signs after the year's observation. As part of the risk assessment for the...

Introduction: Obesity is a major health problem that affects an individual's overall health. Bariatric metabolic surgery is most important and has permanent impact on weight loss in comparison with conservative therapy. The downside is that it often leads to a row nutritional deficiencies requiring long-term supplementation. Object: The aim of the thesis is to map the intake of nutrients in the diet of bariatric patients six months and one year after the procedure. The research is primarily focused on the intake of vitamin D and calcium in diet, vitamin D, parathyroid hormone and calcium levels are also evaluated. Marginally, laboratory values are assessed prior to surgery as deficiencies are known to occur before surgery. Methodology: The research sample consists of 30 respondents who are six months (M6) and one year (Y1) from the procedure. Micronutrients are evaluated from three-day dining records recorded by respondents for at least one week. The research laboratory data was used from the medical information system of the hospital information system. The evaluation parameters for vitamin D-25 (OH)D (limit level was established to > 30 ng/ml). To assess the parathyroid hormone concentration, a minimum limit is set to 1.58 pmol/l, calcium 2.00-2.75 (mmol/l). We were wondering if the profile of...

Psychologist and bariatric tretment of obesity PhDr.Jitka Herlesová Tutor: PhDr.Tamara Hrachovinová, CSc. Abstract The aim of the dissertation thesis is to map psychosocial characteristics associated with obesity and their changes after bariatric surgery. The Empirical part follows the points settled in the Theoretical part. Obesity is a disease, whose prevalence rises. Bariatric and metabolic surgery is one of the most effective treatment of obesity and its comorbidities. The mental diseases are associated with high levels of obesity. The standard part of pre-bariatric examination is the psychological assessment. Several changes accompany the weight loss after bariatric surgery, such as normalization of psychosocial functioning, the decrease of mental disorders but in some cases the changes might be also negative. The Empirical part focuses on the psychosocial characteristics of bariatric surgery candidates assessed during the psychological evaluation and the changes after operation. The data from semi-structured psychological interview, Three factor eating questionnaire, Beck Depression Inventory-II, Obesity Weight Loss Quality of Life and Weight Related Symptom Measure were evaluated. The changes after surgery were assessed after 6, 12 and 24 months. Statistically significant differences were ascertained...

La maladie de Wilson est une maladie héréditaire due à un déficit du transporteur du cuivre, l’ATP7B. Cette maladie se présente sous forme d’insuffisance hépatique aiguë ou chronique, pour lesquels le traitement médical actuel consiste en l’administration d’agents chélateurs, ce qui ne résulte cependant pas en une guérison complète de la maladie. La transplantation orthotopique du foie est le seul traitement définitif actuellement, avec tous les désavantages qu’elle comporte. Un traitement alternatif à cette option est donc souhaitable. Cette étude porte sur la faisabilité de la transplantation d’hépatocytes chez le modèle animal de la maladie de Wilson, le rat Long Evans Cinnamon (LEC), avec pour buts d’en déterminer la sécurité et l’efficacité tant sur le plan clinique (amélioration de la survie, prévention de l’hépatite) que pathologique. Douze rats LEC ont reçu une injection intrasplénique de 2,6 x 105 – 3,6 x 107 hépatocytes prélevés chez des rats donneurs de souche LE. Ils ont été suivis durant 6 mois puis sacrifiés. Ils ont ensuite été comparés à un groupe contrôle de douze autres rats LEC. Aucune différence significative n’a été notée au niveau du poids, du bilan hépatique et des concentrations de cuivre biliaire et hépatique. Cependant, une amélioration de l’activité oxydase de la céruloplasmine post-transplantation a été démontrée chez le groupe de rats transplantés (49,6 ± 31,5 versus 8,9 ± 11,7). Les rats transplantés ont aussi eu une amélioration sur tous les critères histologiques étudiés. Enfin, l’ARNm de l’atp7b a été retrouvé chez 58% des rats transplantés avec un taux d’expression de 11,9% ± 13,6 par rapport à un rat LE normal. L’immunohistochimie a quant à elle démontré la présence de l’atp7b chez tous les rats transplantés. Les résultats obtenus sont considérés favorables à ce traitement alternatif, et indiquent que la transplantation d’hépatocytes est une technique sécuritaire qui peut contribuer à renverser le processus pathologique en cours dans la maladie de Wilson.
Wilson’s disease (WD) is a hereditary metabolic disease caused by a deficiency of copper-transporting ATP7B, resulting in copper accumulating to toxic levels in the liver. Its manifestations range from acute or chronic hepatic insufficiency to fulminant liver failure. The mainstay of therapy is the use of chelating agents. However selected patients may also require orthotopic liver transplantation (OTL), an invasive and complex procedure with life-long implications. Hepatocyte transplantation is an appealing alternative to OLT. Its safety and efficacy were evaluated in the animal model of WD, the Long Evans Cinnamon (LEC) rat. Twelve LEC rats received an intrasplenic injection of 2,6 x 105 – 3,6 x 107 hepatocytes obtained from LE donor rats. They were followed for 6 months before sacrifice. They were then compared to a control group of twelve rats. No difference was found when comparing their weights, biochemical parameters such as liver function tests and bilirubin, as well as their biliary and hepatic copper concentrations. However, the ceruloplasmin oxydase activity was improved in the transplanted rats (49,6 ± 31,5 versus 8,9 ± 11,7). After sacrifice, histologic evaluation and demonstration of atp7b mRNA in the recipient liver were performed. There was evidence of histological improvement and atp7b mRNA was found in 58% of transplanted rats with an expression of 11,9% ± 13,6 when compared to a normal LE rat. Evidence of successful engraftment of the transplanted cells was found in every transplanted rat using the technique of immunohistochemistry. These encouraging results are in accordance with previous studies on hepatocyte transplantation in the LEC rat. Its application to the human clinical setting is the next step, as it has already been tried in other metabolic liver diseases.