Liver specific, systemic and genetic contributors to alcohol-related liver disease progression

Abstract

Alcohol-related liver disease (ALD) impacts millions of patients worldwide each year and the numbers are increasing. Disease stages range from steatosis via steatohepatitis and fibrosis to cirrhosis, severe alcohol-associated hepatitis and liver cancer. ALD is usually diagnosed at an advanced stage of progression with no effective therapies. A major research goal is to improve diagnosis, prognosis and also treatments for early ALD. This however needs prioritization of this disease for financial investment in basic and clinical research to more deeply investigate mechanisms and identify biomarkers and therapeutic targets for early detection and intervention. Topics of interest are communication of the liver with other organs of the body, especially the gut microbiome, the individual genetic constitution, systemic and liver innate inflammation, including bacterial infections, as well as fate and number of hepatic stellate cells and the composition of the extracellular matrix in the liver. Additionally, mechanical forces and damaging stresses towards the sophisticated vessel system of the liver, including the especially equipped sinusoidal endothelium and the biliary tract, work together to mediate hepatocytic import and export of nutritional and toxic substances, adapting to chronic liver disease by morphological and functional changes. All the aforementioned parameters contribute to the outcome of alcohol use disorder and the risk to develop advanced disease stages including cirrhosis, severe alcoholic hepatitis and liver cancer. In the present collection, we summarize current knowledge on these alcohol-related liver disease parameters, excluding the aspect of inflammation, which is presented in the accompanying review article by Lotersztajn and colleagues.

Zusammenfassung

Die alkoholbedingte Lebererkrankung (ALD) betrifft jedes Jahr weltweit Millionen von Patienten, und ihre Zahl nimmt zu. Die Krankheitsstadien reichen von Steatose über Steatohepatitis und Fibrose bis hin zu Zirrhose, schwerer alkoholbedingter Hepatitis und Leberkrebs. ALD wird in der Regel erst in einem fortgeschrittenen Stadium diagnostiziert, in dem es keine wirksamen Therapien gibt. Ein wichtiges Forschungsziel ist die Verbesserung der Diagnose, der Prognose und auch der Behandlung von ALD im Frühstadium. Dies erfordert jedoch eine Priorisierung dieser Krankheit für finanzielle Investitionen in die Grundlagen- und klinische Forschung, um die Mechanismen genauer zu untersuchen und Biomarker und therapeutische Ziele für die Früherkennung und -behandlung zu ermitteln. Themen von Interesse sind die Kommunikation der Leber mit anderen Organen des Körpers, insbesondere das Darmmikrobiom, die individuelle genetische Konstitution, systemische und angeborene Entzündungen in der Leber einschließlich bakterieller Infektionen, sowie das Schicksal und die Anzahl der hepatischen Sternzellen und die Zusammensetzung der extrazellulären Matrix in der Leber. Darüber hinaus wirken mechanische Kräfte und schädigende Belastungen auf das hochentwickelte Gefäßsystem der Leber, einschließlich des besonders ausgestatteten sinusoidalen Endothels und der Gallenwege, zusammen, um den hepatozytären Import und Export von Nähr- und Giftstoffen zu vermitteln und sich durch morphologische und funktionelle Veränderungen an die chronische Lebererkrankung anzupassen. Alle vorgenannten Parameter tragen zu den Folgen des Alkoholkonsums und dem Risiko der Entwicklung fortgeschrittener Krankheitsstadien einschließlich Zirrhose, schwerer alkoholischer Hepatitis und Leberkrebs bei. In der vorliegenden Sammlung fassen wir den aktuellen Wissensstand zu diesen alkoholbedingten Parametern der Lebererkrankung zusammen, wobei wir den Aspekt der Entzündung ausklammern, der in dem begleitenden Übersichtsartikel von Lotersztajn und Kollegen dargestellt wird.

Schlüsselwörter

Alkoholbedingte Lebererkrankung - extrazelluläre Matrix - hepatische Sternzellen - Mikrobiom - Gallenwege - Genetische Konstitution

Keywords

Alcohol-related liver disease - Extracellular matrix - Hepatic stellate cells - Gut microbiota - Biliary system - Host genetics

Publication History

Received: 16 November 2021

Accepted: 06 December 2021

Article published online:
18 January 2022

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