Der Einfluss von Proteinkinase-C-Isoformen auf die Lokalisation und Funktion des ABCC2/MRP2 Transporters in einem Modell der septischen Cholestase

Im Verlauf der Wirtsreaktion auf eine schwere Infektion kommt es früh zu einer exkretorischen Dysfunktion der Leber. Das Auftreten der septischen Cholestase ist mit einem ungünstigen klinischen Verlauf assoziiert. Die, dem Defekt der hepato- und cholangiozellulären Transportsysteme zu Grunde liegenden, pathophysiologischen Mechanismen sind noch nicht vollständig entschlüsselt und Gegenstand aktueller Forschung. Rückschlüsse über beteiligte Komponenten sind anhand der besser charakterisierten Signalkaskade der physiologischen Gallesekretion möglich und weisen der Proteinkinase-C-Familie eine entscheidende Rolle in der Regulation der Signalverarbeitung zu. Ein Grund für die anhaltend hohe Mortalität und Zunahme der Inzidenz der Sepsis ist das Fehlen von adjunktiven, immunmodulatorischen Sepsistherapeutika zur Behandlung des konsekutiven Organversagens. Die Inhibition der Proteinkinase-C wird aktuell als therapeutische Option zur kausalen Behandlung der septischen Cholestase diskutiert. Die Wiederherstellung der hepatischen Exkretionsleistung könnte das Ausmaß des Organversagens verhindern und dazu beitragen, die anhaltend hohe Mortalität der Sepsis zu senken. Zur Entwicklung neuer therapeutische Ansätze, die in die Signalverarbeitung von Zellen eingreifen, ist ein genaues Verständnis für die, der septischen Cholestase zugrundeliegenden Mechanismen notwendig. Vor diesem Hintergrund stellt sich die Frage, inwiefern die Proteinkinase-C die frühe inflammatorische Signalkaskade mitgestaltet, die zu einer Abnahme der Exkretionsleistung führt. Auch soll unter Kontrolle der Werte für die hepatozelluläre Integrität geklärt werden, ob die gezielte Inhibition einzelner Isoformen der Proteinkinase-C positiven Einfluss auf die Sepsis-assoziierte, exkretorische Dysfunktion ausübt. ..

Severe acute hepatitis and acute liver failure of unknown origin in children : a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel, April 2022

Publisher Copyright: © 2022 European Centre for Disease Prevention and Control (ECDC). All rights reserved.To detect potential concern about severe acute hepatitis in children, we conducted a survey among 50 ERN RARE-LIVER centres. By 26 April 2022, 34 centres, including 25 transplant centres, reported an estimated median of 3-5, 0-2 and 3-5 cases in 2021, 2020 and 2019 and a mean of 2 (range: 0-8) cases between January and April 2022 (mean in 10 large liver transplant centres: 3). Twelve centres reported suspicion of an increase, but no rise. Following a report by the United Kingdom (UK) on 5 April 2022 on the occurrence of cases of severe acute hepatitis in children aged 16 years or under, the World Health Organization (WHO) raised concerns about the possibility of an epidemic [1,2]. By 21 April, 169 possible or confirmed cases were reported fulfilling the WHO case definition [3]. The cause of the hepatitis is unknown but a link to a virus infection has been suggested due to the epidemiological pattern of cases [4,5]. The hepatitis can progress to paediatric acute liver failure (pALF) necessitating urgent liver transplantation to avoid multi-organ failure [6]. We intended to assess whether a rise in incidence of severe acute hepatitis or pALF could be observed between 1 January and 26 April 2022 in comparison to previous years, within the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) [7].Peer reviewe

Severe acute hepatitis and acute liver failure of unknown origin in children:a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel, April 2022

To detect potential concern about severe acute hepatitis in children, we conducted a survey among 50 ERN RARE-LIVER centres. By 26 April 2022, 34 centres, including 25 transplant centres, reported an estimated median of 3-5, 0-2 and 3-5 cases in 2021, 2020 and 2019 and a mean of 2 (range: 0-8) cases between January and April 2022 (mean in 10 large liver transplant centres: 3). Twelve centres reported suspicion of an increase, but no rise. Following a report by the United Kingdom (UK) on 5 April 2022 on the occurrence of cases of severe acute hepatitis in children aged 16 years or under, the World Health Organization (WHO) raised concerns about the possibility of an epidemic [1,2]. By 21 April, 169 possible or confirmed cases were reported fulfilling the WHO case definition [3]. The cause of the hepatitis is unknown but a link to a virus infection has been suggested due to the epidemiological pattern of cases [4,5]. The hepatitis can progress to paediatric acute liver failure (pALF) necessitating urgent liver transplantation to avoid multi-organ failure [6]. We intended to assess whether a rise in incidence of severe acute hepatitis or pALF could be observed between 1 January and 26 April 2022 in comparison to previous years, within the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) [7]

Hepatic safety and efficacy of immunomodulatory drugs used in patients with autoimmune hepatitis.

BACKGROUND AND AIMS There is little data on the hepatic efficacy and safety of immunomodulatory drugs used in patients with autoimmune hepatitis (AIH), despite their established use in dermatology, rheumatology and inflammatory bowel diseases (IBD). Our aim was to collect real-life data on the experience of expert centres in treating AIH patients with these drugs, considered unconventional for AIH management. METHODS Online survey among hepatology centres being part of the European Reference Network on Hepatological Diseases (ERN RARE-LIVER). RESULTS 25 AIH patients have been reported. Ten were female, median age at diagnosis was 28 years; median follow-up was 17 months. All had initially received AIH-standard treatment. AIH-unconventional treatment was initiated for concomitant autoimmune diseases in 15 cases: nine for IBD (five vedolizumab and four ustekinumab), and one each for following diseases: autoinflammatory syndrome (tocilizumab), chronic urticaria (omalizumab), rheumatoid arthritis (abatacept), psoriasis (guselkumab), psoriatric arthritis (secukinumab, followed by ustekinumab) and alopecia (ruxolitinib). Three patients were treated with immunomodulatory drugs for side effects of previous treatments, including two patients with IBD treated with vedolizumab and ustekinumab, respectively, and one treated with belimumab. At the end of follow-up, 13 patients were in complete biochemical response, the patient on omalizumab had a relapse, and four patients with concomitant IBD had insufficient response. Seven patients were treated for lack of biochemical remission, of whom six with belimumab, all initially reaching complete biochemical response, but five relapsing during follow-up; and one with secukinumab, having concomitant rheumatoid arthritis and ankylosing spondylitis, reaching complete biochemical response. Only the patient on abatacept received unconventional treatment as monotherapy. Side effects were reported in two patients on belimumab: one recurrent soft tissue infections, one fatigue and arthralgia. CONCLUSION Among 25 AIH patients who were treated with immunomodulatory drugs for different reasons, the majority had a fovorable course, relapse was frequent in difficult-to-treat patients who received belimumab, and four with concomitant IBD had insufficient response

Severe acute hepatitis and acute liver failure of unknown origin in children : a questionnaire-based study within 34 paediatric liver centres in 22 European countries and Israel, April 2022

Publisher Copyright: © 2022 European Centre for Disease Prevention and Control (ECDC). All rights reserved.To detect potential concern about severe acute hepatitis in children, we conducted a survey among 50 ERN RARE-LIVER centres. By 26 April 2022, 34 centres, including 25 transplant centres, reported an estimated median of 3-5, 0-2 and 3-5 cases in 2021, 2020 and 2019 and a mean of 2 (range: 0-8) cases between January and April 2022 (mean in 10 large liver transplant centres: 3). Twelve centres reported suspicion of an increase, but no rise. Following a report by the United Kingdom (UK) on 5 April 2022 on the occurrence of cases of severe acute hepatitis in children aged 16 years or under, the World Health Organization (WHO) raised concerns about the possibility of an epidemic [1,2]. By 21 April, 169 possible or confirmed cases were reported fulfilling the WHO case definition [3]. The cause of the hepatitis is unknown but a link to a virus infection has been suggested due to the epidemiological pattern of cases [4,5]. The hepatitis can progress to paediatric acute liver failure (pALF) necessitating urgent liver transplantation to avoid multi-organ failure [6]. We intended to assess whether a rise in incidence of severe acute hepatitis or pALF could be observed between 1 January and 26 April 2022 in comparison to previous years, within the European Reference Network on Hepatological Diseases (ERN RARE-LIVER) [7].Peer reviewe