Mechanisms and aetiology-dependent treatment of acute liver failure

Abstract

This review compiles the mechanisms of acute liver failure (ALF) as well as the current and potential therapeutic approaches, including aetiology-specific treatment, and the issues encountered with such approaches. On a cellular level, ALF is characterized by massive hepatocyte death due to different types of cellular demise. Compensatory hyperplasia and functional recovery are possible when the regenerative capacity is sufficient to sustain hepatic function. ALF has a high mortality of about 30% and can lead to death in a very short time despite maximum therapeutic intervention. Besides aetiology-specific therapy and intensive care, the therapeutic option of emergency liver transplantation has significantly improved the prognosis of patients with ALF. However, due to limiting factors such as organ shortage, many patients die on the waiting list. In addition to graft assessment, machine perfusion may have the potential to recondition marginal organs and thus expand the organ donor pool.

Keywords: acute liver failure; aetiology; liver transplantation; prediction of prognosis; rebalanced haemostasis; survival markers.

FIGURE 1

Overview on mechanisms involved during acute liver failure. Acute liver failure (ALF) is characterized by severe acute liver injury resulting in extensive hepatocyte cell death and loss of liver function, occurring suddenly without prior injury or chronic disease. Various modes of hepatocyte cell death, including apoptosis, necrosis, and necroptosis, potentially modulated by the NLRP3 inflammasome, contribute to this process. The widespread demise of hepatocytes triggers the proliferation of differentiated hepatocytes as an initial compensatory response, which might be inadequate to counterbalance the cell loss. Consequently, activation of the hepatic stem cell compartment ensues. Elimination of cellular debris and apoptotic bodies originating from the deceased hepatocytes is handled by resident Kupffer cells, infiltrating bone marrow‐derived macrophages and hepatic stellate cells (HSCs). Activated HSCs adopt a fibroblast‐like phenotype and produce collagen to promote tissue integrity in the damaged liver. Persistent injury, if unabated, and uncontrolled collagen production by HSCs lead to the formation of scar tissue and fibrogenesis, replacing functional liver mass with extracellular matrix. The extensive hepatocyte cell death results in the release of enzymes such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT), causing a significant elevation of their serum concentrations. The diminished number and compromised function of hepatocytes impairs ammonia detoxification, thereby contributing to the development of hepatic encephalopathy (HE). Moreover, the reduced hepatocyte capacity to synthesize both pro‐ and anticoagulant factors manifests as increased International Normalized Ratio (INR) and coagulation abnormalities. Pictograms/cartoons taken from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 France Licence.

FIGURE 2

Etiologies and specific treatments for acute liver failure. This schematic overview illustrates various causative factors that can lead to severe acute liver tissue damage, culminating in acute liver failure (ALF). Depending on the specific underlying cause, immediate and tailored therapeutic approaches can effectively address the ALF, potentially obviating the need for (emergency) liver transplantation, which serves as a last‐resort measure in cases where ALF lacks spontaneous remission or when the cause remains unidentified. For comprehensive treatment protocols, refer to Table 1. DILI, drug‐induced liver injury; HE, hepatic encephalopathy; TIPS, transjugular intrahepatic portosystemic shunt. Pictograms/cartoons taken from Servier Medical Art by Servier, licensed under a Creative Commons Attribution 3.0 France Licence. Death cap picture from Danny Cicchetti, CC BY‐SA 4.0 https://creativecommons.org/licenses/by‐sa/4.0, via Wikimedia Commons.