Current and prospective therapies for acute liver failure
Introduction
Acute liver failure (ALF) is commonly defined as the sudden, rapid deterioration and loss of hepatic function usually in a previously healthy person, without prior liver disease. ALF is characterized by altered mental status and coagulopathy, with an international normalized ratio (INR) ≥ 1.5. It can be subdivided further based on the timing of onset; ALF with signs and symptoms developing within one week, 1–3 weeks, and 3–26 weeks may be categorized as hyper-acute, acute, and subacute, respectively.1, 2
In the United States and Western Europe, acetaminophen overdose is the most common cause of ALF, accounting for almost half of all cases. Worldwide, the most common etiology is viral hepatitis. Other common causes of ALF include autoimmune hepatitis, ischemic hepatitis, Wilson disease and Budd–Chiari Syndrome.3
There are approximately 2000 new ALF cases each year in our country; worldwide estimates indicate 1–8 persons per million develop ALF each year.4 Prior to the advent of liver transplantation, ALF survival was dismal, only about 20%. With access to liver transplantation and enhancements in the care offered by modern intensive care units (ICU), ALF mortality has declined so that it is common to see survival rates in the range of 80%.5
Our goal is to review the presentation, diagnosis and causes of ALF. We will also discuss the appropriate initial evaluation and tools that can help predict ALF prognosis and the timing of liver transplantation, if needed. The greater part of this review will summarize current and future therapies.
Section snippets
Diagnosis
Generally, ALF is readily diagnosed from pertinent history and physical findings along with consistent laboratory abnormalities. Most commonly there is no antecedent liver disease. The absence of chronic liver disease makes it different from acute-on-chronic liver failure which is a different entity. Occasionally, aspects of the history alone raise suspicion for ALF (e.g. use of excessive amounts of acetaminophen) but sometimes the history may be unremarkable. Physical examination may reveal
Management based on etiology of acute liver failure
Table 2 summarizes the most common etiologies of ALF and recommendations for their management.
Cerebral edema and intracranial hypertension
Cerebral edema is a feared complication of ALF with HE; consequences of cerebral edema and increased intracranial pressure range from ischemic and hypoxic injury to uncal herniation and death. The likelihood of cerebral edema is proportional to the degree of HE – 25–35% and 65–75% of patients with grades III and IV HE, respectively, develop cerebral edema. Although the mechanisms are uncertain, ammonia and glutamine levels as well as the degree of oxidative stress are implicated as causes of
Prognostic models
Prognostic models quickly and accurately predict the need for liver transplantation in ALF. This is extremely important since waiting too long for transplant can be lethal but transplanting too soon can increase morbidity for someone who may have recovered without transplantation. Etiology of liver injury is a primary predictor of outcome in ALF; transplant-free survival is best for acetaminophen-, hepatitis A-, shock-, and pregnancy-related liver disease.2 Other key outcome factors are
Liver transplantation
The estimated overall survival of patients with ALF is about 60%, of which 40% is by spontaneous recovery. Of those who undergo transplantation, one-year post-transplantation survival is 74–84%.5
Barshes et al. described four factors associated with poor outcomes in ALF, including age > 50 years, need for life support, body mass index (BMI) ≥ 30 kg/m2, and creatinine > 2.0 mg/dL. Five-year survival was 83% in patients meeting none of these criteria but 47% in those meeting all four adverse
Prospective therapies
While improved critical care and the above advances in transplantation have enhanced the ability to manage ALF, there is much room for improvement. Therapies currently under investigation include hepatocyte transplantation and extracorporeal support devices. Results appear promising but additional work is needed to determine the role of these new therapies in practice.
Financial support
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Cited by (10)
A dopamine-precursor-based nanoprodrug for in-situ drug release and treatment of acute liver failure by inhibiting NLRP3 inflammasome and facilitating liver regeneration
2021, BiomaterialsCitation Excerpt :The main causes of ALF include hepatitis virus infection which is responsible for majority cases of ALF in developing countries, and the drug-induced liver injury which accounts for about one-half of ALF incidents in Western countries [3,4]. With advances in liver transplantation and intensive clinical management, the previously very high mortality rate (~80%) caused by ALF has now declined, but the overall death rate remains at a high level of around 40% [5]. The limited availability of liver transplantation has led to the development of other therapies, including the medication (drug) treatment [6,7].
Critical role of IL-1β in the pathogenesis of Agrocybe aegerita galectin-induced liver injury through recruiting T cell to liver
2020, Biochemical and Biophysical Research CommunicationsCitation Excerpt :The most common etiology in worldwide is viral hepatitis. Other common causes of ALF include autoimmune hepatitis, ischemic hepatitis, Wilson disease and Budd-Chiari Syndrome [2]. Treatment strategies of ALF vary due to the diversity of etiology.
Nicotine attenuates concanavalin A-induced liver injury in mice by regulating the α7-nicotinic acetylcholine receptor in Kupffer cells
2020, International ImmunopharmacologyCitation Excerpt :Acute liver failure (ALF) or fulminant hepatic failure (FHF) is commonly characterized by a sudden and rapid development of hepatic dysfunction, specifically with altered mental status and coagulopathy in a patient without liver disease. Since a reasonable option for liver transplantation has lowered the death rate, the survival rates of ALF have risen to 80% from as low as 15% in the last decade [1–3]. As one of the common reasons for ALF, autoimmune hepatitis is a necroinflammatory disease of the liver that is usually accompanied by increased aminotransferase levels, interface hepatitis, species non-specific autoantibody production, and elevated IgG levels [4].
The hepatoprotective effect of polysaccharides from Pleurotus ostreatus on carbon tetrachloride-induced acute liver injury rats
2019, International Journal of Biological MacromoleculesCitation Excerpt :Worldwide morbidity and mortality of hepatic failure caused by ALI are very high. A total of one to eight persons per million develop hepatic failure each year [4]. A previous study verified that oxidative damage caused by reactive oxygen species (ROS) has a great part in the development of ALI [5].
Acute Liver Failure Guidelines
2023, American Journal of Gastroenterology