Acute and acute-on-chronic liver failure: Pathogenesis, management and perspectives

Abstract

Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) represent critical junctures in the spectrum of liver diseases, characterized by rapid deterioration of liver function and often multi-organ dysfunction. Despite advances in medical care, they remain significant challenges in clinical practice, necessitating a deeper understanding of their pathophysiology and the development of effective therapeutic strategies. This special issue intents to address these topics in 15 selected reviews.

The first two reviews are ALF pathogenesis and therapy in focus.^{1, 2} ALF is a rare but life-threatening condition characterized by the sudden loss of liver function in individuals with no pre-existing liver disease. It is associated with a high mortality rate, typically ranging from 50% to 80%. The aetiology of ALF can be diverse, including viral hepatitis, drug-induced liver injury, autoimmune hepatitis and acute ischaemic liver injury among others (Figure 1). Regardless of the underlying cause, the hallmark of ALF is massive hepatocyte death, leading to impaired synthetic and metabolic functions of the liver. The clinical presentation of ALF can vary widely, but common features include jaundice, coagulopathy, hepatic encephalopathy, and often, rapid clinical deterioration. The management of ALF involves intensive supportive care, including measures to maintain hemodynamic stability, correct coagulopathy and manage complications such as cerebral oedema and hepatic encephalopathy.¹ Liver transplantation remains the only definitive treatment option for many patients with ALF, offering the possibility of long-term survival. However, the availability of donor organs and the timing of transplantation are crucial factors that significantly impact outcomes. In recent years, there has been growing interest in the development of artificial liver support systems as a bridge to liver transplantation or to support liver function and promote regeneration in patients with ALF. These systems aim to remove toxins, correct metabolic imbalances and provide temporary liver function while awaiting recovery or transplantation. Various modalities, including extracorporeal liver support devices and bioartificial liver systems, have been investigated, but their clinical efficacy remains a subject of debate.²

ACLF, on the other hand, represents a distinct clinical syndrome characterized by acute deterioration of liver function in patients with underlying chronic liver disease, most commonly cirrhosis. Hernaez and colleagues summarized in their comprehensive review definition, diagnosis and epidemiology of ACLF.³ ACLF typically develops in the setting of acute decompensation but may also develop from the stage of chronic decompensation, so-called non-acute decompensation.⁴ For the development of ACLF a precipitating event, such as bacterial infection, alcoholic hepatitis, or gastrointestinal bleeding, triggers systemic inflammatory response and exacerbates liver injury. But also necessary medical interventions (Figure 2) may induce injury and precipitate ACLF as summarized by Praktiknjo et al.⁵ The dysregulated immune response leads to widespread tissue damage and organ dysfunction, and may induce hepatic and extra-hepatic organ failures, driving the extreme high short-term mortality rate, ranging from 30% to 50%.⁶ Alcoholic hepatitis is a specific trigger and still unaddressed clinical condition.⁷ Similarly to alcoholic hepatitis,⁷ also the pathophysiology of ACLF is complex and multifactorial, involving interactions between the immune system, gut microbiota and systemic inflammation.

In recent years, significant progress has been made, and we expect the technological (omics) and digital (artificial intelligence) progress to improve understanding, diagnosis and potentially design therapeutic approaches.⁸ Especially using large cohorts and omics data sets will facilitate the construction of the algorithms to predict the prognosis of patients with acute decompensation and ACLF. Existing and potentially future progress is reviewed by Valainathan et al.⁹

Current management of ACLF focuses on treating the underlying precipitating factors, providing supportive care and organ support and, in some cases, considering liver transplantation as a life-saving intervention.¹⁰ The role of systemic inflammation and immune dysregulation in the pathogenesis of ACLF has been demonstrated over the last years, and this leads to the exploration of novel therapeutic targets, such as interleukin-22 as reviewed by Hwang et al.¹¹ Strategies aimed at modulating the immune response, such as corticosteroids, immunomodulatory agents and anti-inflammatory cytokines, have shown promise in preclinical studies and early-phase clinical trials.¹² The treatment approaches for ACLF are multimodal, and indeed, one may shape the strategy based on the molecular mechanism supporting a clear rationale (Figure 3), as nicely reviewed by Morrison et al.¹³ In addition to pharmacological interventions, there has been increasing interest in the use of extracorporeal liver support systems as a potential therapeutic strategy for ACLF. These devices aim to provide temporary liver function support, remove toxins and inflammatory mediators, and promote liver regeneration. While early studies have shown promising results, larger randomized controlled trials are needed to establish their role in the management of ACLF.^{14, 15}

In conclusion, ALF and ACLF represent critical clinical challenges associated with high morbidity and mortality. Despite advances in medical care, there remains a need for further research to better understand the pathophysiology of these conditions and develop more effective therapeutic strategies. The development of artificial liver support systems and targeted immunomodulatory therapies holds promise for improving outcomes in patients with ALF and ACLF, but further studies are needed to validate their efficacy and safety in clinical practice.

Jonel Trebicka was supported by the German Research Foundation (DFG) project ID 403224013—SFB 1382 (A09), by the German Federal Ministry of Education and Research (BMBF) for the DEEP-HCC project and by the Hessian Ministry of Higher Education, Research and the Arts (HMWK) for the ENABLE and ACLF-I cluster projects. The MICROB-PREDICT (project ID 825694), DECISION (project ID 847949), GALAXY (project ID 668031), LIVERHOPE (project ID 731875) and IHMCSA (project ID 964590) projects have received funding from the European Union's Horizon 2020 research and innovation program. The manuscript reflects only the authors' views, and the European Commission is not responsible for any use that may be made of the information it contains. The funders had no influence on study design, data collection and analysis, decision to publish or preparation of the manuscript.

Jonel Trebicka has received speaking and/or consulting fees from Versantis, Gore, Boehringer-Ingelheim, Falk, Grifols, Genfit and CSL Behring.

This review article does not contain any primary patient data nor did it involve the use of human or animal subjects. As such, ethical approval was not required for the production of this article.

This review article does not contain any primary patient data, nor did it involve the use of human or animal subjects.

This article does not contain materials from other sources.

The authors have no writing assistance to disclose.