Inflammation in alcohol-associated liver disease progression

Abstract

Chronic alcohol consumption induces stress and damage in alcohol metabolising hepatocytes, which leads to inflammatory and fibrogenic responses. Besides these direct effects, alcohol disrupts intestinal barrier functions and induces gut microbial dysbiosis, causing translocation of bacteria or microbial products through the gut mucosa to the liver and, which induce inflammation indirectly. Inflammation is one of the key drivers of alcohol-associated liver disease progression from steatosis to severe alcoholic hepatitis. The current standard of care for the treatment of severe alcoholic hepatitis is prednisolone, aiming to reduce inflammation. Prednisolone, however improves only short-term but not long-term survival rates in those patients, and even increases the risk for bacterial infections. Thus, recent studies focus on the exploration of more specific inflammatory targets for the treatment of severe alcoholic hepatitis. These comprise, among others interference with inflammatory cytokines, modulation of macrophage phenotypes or targeting of immune cell communication, as summarized in the present overview. Although several approaches give promising results in preclinical studies, data robustness and ability to transfer experimental results to human disease is still not sufficient for effective clinical translation.

Zusammenfassung

Chronischer Alkoholkonsum verursacht Stress und schädigt die den Alkohol metabolisierenden Hepatozyten, was zu entzündlichen und fibrogenen Reaktionen führt. Neben diesen direkten Auswirkungen stört Alkohol die Funktionen der Darmbarriere und führt zu einer Dysbiose des Darmmikrobioms, wodurch Bakterien oder mikrobielle Produkte durch die Darmschleimhaut in die Leber gelangen und so über den indirekten Weg Entzündungsreaktionen hervorrufen. Entzündung ist eine der Hauptursachen für das Fortschreiten der alkoholbedingten Lebererkrankung von der Steatose zur schweren alkoholischen Hepatitis. Die derzeitige Standardbehandlung der schweren alkoholischen Hepatitis ist Prednisolon, um die Entzündung zu reduzieren. Prednisolon verbessert jedoch nur die kurzfristigen, nicht aber die langfristigen Überlebensraten der Patienten und erhöht sogar das Risiko für bakterielle Infektionen. Daher konzentrieren sich Forschung und Studien neuerdings auf spezifischere Entzündungsziele zur Behandlung der schweren alkoholischen Hepatitis. Dazu gehören unter anderem die Beeinflussung entzündlicher Zytokine, die Modulation von Makrophagen-Phänotypen oder die gezielte Beeinflussung der Immunzellkommunikation, wie in der vorliegenden Übersicht zusammengefasst. Obwohl verschiedene Ansätze in präklinischen Studien vielversprechende Ergebnisse liefern, ist die Robustheit der Daten und damit die Übertragbarkeit auf die menschliche Krankheit für eine effektive klinische Umsetzung noch nicht ausreichend.

Schlüsselwörter

alkoholische Lebererkrankung - alkoholische Hepatitis - Entzündung - Zytokine - Makrophagen - Immunzellkommunikation

Keywords

alcoholic liver disease - alcoholic hepatitis - inflammation - cytokines - macrophages - immune cell communication

Publication History

Received: 15 October 2021

Accepted: 06 December 2021

Article published online:
18 January 2022

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