Acute-on-Chronic Liver Failure: Pathophysiological Mechanisms and Management

Abstract

Acute-on-chronic liver failure (ACLF) is a multifaceted condition with poor treatment options and high short-term mortality. ACLF can develop in patients with or without liver cirrhosis, where patients with decompensated cirrhosis display a higher risk of short-term mortality. Pathophysiological mechanisms include systemic inflammation due to bacterial and fungal infections and acute hepatic insult with drug, alcohol, and viral hepatitis. Cryptogenic factors also contribute to the development of ACLF. The clinical outcome of patients with ACLF gets further complicated by the occurrence of variceal hemorrhage, hepatorenal syndrome, hepatic encephalopathy, and systemic immune dysfunction. Regardless of the better understanding of pathophysiological mechanisms, no specific and definitive treatment is available except for liver transplantation. The recent approach of regenerative medicine using mesenchymal stem cells (MSCs) could be advantageous for the treatment of ACLF as these cells can downregulate inflammatory response by inducing antiinflammatory events and prevent hepatic damage and fibrosis by inhibiting hepatic stellate cell activation and collagen synthesis. Moreover, MSCs are involved in tissue repair by the process of liver regeneration. Considering the broad therapeutic potential of MSCs, it can serve as an alternative treatment to liver transplant in the near future, if promising results are achieved.

Current and future perspectives on acute-on-chronic liver failure: Challenges of transplantation, machine perfusion, and beyond

“…Recent evidence suggests systemic inflammation is the key to AD and ACLF disease progression[ 3 , 10 , 26 ]. Briefly, in patients with sepsis as the precipitant event, the inflammatory response is triggered by the recognition of pathogen-associated molecular patterns by pattern recognition receptors.…”

The Mechanisms of Systemic Inflammatory and Immunosuppressive Acute-on-Chronic Liver Failure and Application Prospect of Single-Cell Sequencing

“…Glucocorticoid-mediated immunosuppression may increase the chance of bacterial infection with alcoholic hepatitis. Therefore, corticosteroids are best used for short periods of the first stage [ 140 , 141 ].…”

“…For this reason, it is necessary to evaluate the efficacy of steroids with Lille score, which is based on age, total bilirubin levels, baseline creatinine levels, albumin levels, prothrombin time, and repeated total bilirubin levels [ 142 , 143 ]. Patients can be classified as complete responders (≤0.16), partial responders (0.16–0.56), or nonresponders (>0.56) based on the Lille score to determine whether to continue or discontinue corticosteroid therapy [ 140 ]. Corticosteroid responses in ACLF patients are further reduced as the severity of ACLF increased.…”

Survival Fate of Hepatic Stem/Progenitor and Immune Cells in a Liver Fibrosis/Cirrhosis Animal Model and Clinical Implications

“…The healthy liver performs over 500 different functions to maintain its homeostasis [1,2], and any assault could not only impact the architecture of hepatic cells [3] but also injure niche cells, like inflammatory and immune cells such as CD8-positive cytotoxic T lymphocyte subset (CD8 + T cells) which have been recently highlighted [4]. Liver cirrhosis is an end-stage liver disease (ESLD) and a major cause of morbidity and mortality globally [5].…”