Elsevier

Disease-a-Month

Volume 64, Issue 12, December 2018, Pages 493-522
Disease-a-Month

Current and prospective therapies for acute liver failure

https://doi.org/10.1016/j.disamonth.2018.04.002Get rights and content

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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References (177)

  • NM Kemmer et al.

    Hepatitis A

    Infect Dis Clin North Am

    (2000)
  • HL Chan et al.

    Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial

    Lancet Gastroenterol Hepatol

    (2016)
  • S Kumar Acharya et al.

    Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death

    J Hepatol

    (2007)
  • M Patil et al.

    A review and current perspective on Wilson disease

    J Clin Exp Hepatol

    (2013)
  • EA Roberts et al.

    Division of gastroenterology and nutrition HfSC, Toronto, Ontario, Canada. A practice guideline on Wilson disease

    Hepatology

    (2003)
  • M Svetel et al.

    Neuropsychiatric aspects of treated Wilson's disease

    Parkinsonism Relat Disord

    (2009)
  • JM Walshe et al.

    Dangers of non-compliance in Wilson's disease

    Lancet

    (1986)
  • T Al-Chalabi et al.

    Impact of gender on the long-term outcome and survival of patients with autoimmune hepatitis

    J Hepatol

    (2008)
  • F Alvarez et al.

    International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis

    J Hepatol

    (1999)
  • AJ Czaja et al.

    Frequency and significance of antibodies to liver/kidney microsome type 1 in adults with chronic active hepatitis

    Gastroenterology

    (1992)
  • JL Wolf

    Liver disease in pregnancy

    Med Clin North Am

    (1996)
  • BM. Sibai

    The HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets): much ado about nothing

    Am J Obstet Gynecol

    (1990)
  • WM Lee et al.

    Introduction to the revised American Association for the Study of Liver Diseases Position Paper on acute liver failure 2011

    Hepatology

    (2012)
  • WM Lee et al.

    AASLD Position Paper: The Management of Acute Liver Failure: Update 2011

  • WM Lee et al.

    Acute liver failure: Summary of a workshop

    Hepatology

    (2008)
  • G Ostapowicz et al.

    Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States

    Ann Intern Med

    (2002)
  • W Bernal et al.

    Acute liver failure

    N Engl J Med

    (2013)
  • P Nourjah et al.

    Estimates of acetaminophen (Paracetomal)-associated overdoses in the United States

    Pharmacoepidemiol Drug Saf

    (2006)
  • WM. Lee

    Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure

    Hepatology

    (2004)
  • AM Larson et al.

    Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study

    Hepatology

    (2005)
  • LJ Chun et al.

    Acetaminophen hepatotoxicity and acute liver failure

    J Clin Gastroenterol

    (2009)
  • PI Dargan et al.

    Acetaminophen poisoning: an update for the intensivist

    Crit Care

    (2002)
  • BH Rumack et al.

    Acetaminophen poisoning and toxicity

    Pediatrics

    (1975)
  • DR Douglas et al.

    A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol)

    Acad Emerg Med

    (1996)
  • DJ Jollow et al.

    Acetaminophen-induced hepatic necrosis. II. Role of covalent binding in vivo

    J Pharmacol Exp Ther

    (1973)
  • WZ Potter et al.

    Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters

    Pharmacology

    (1974)
  • KJ Heard

    Acetylcysteine for acetaminophen poisoning

    N Engl J Med

    (2008)
  • BH Rumack et al.

    Acetaminophen overdose. 662 cases with evaluation of oral acetylcysteine treatment

    Arch Intern Med

    (1981)
  • WM Lee et al.

    Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure

    Gastroenterology

    (2009)
  • F Enjalbert et al.

    Treatment of amatoxin poisoning: 20-year retrospective analysis

    J Toxicol Clin Toxicol

    (2002)
  • L Santi et al.

    Acute liver failure caused by Amanita phalloides poisoning

    Int J Hepatol

    (2012)
  • A Himmelmann et al.

    Lethal ingestion of stored Amanita phalloides mushrooms

    Swiss Med Wkly

    (2001)
  • W Litten

    The most poisonous mushrooms

    Sci Am

    (1975)
  • L Giannini et al.

    Amatoxin poisoning: a 15-year retrospective analysis and follow-up evaluation of 105 patients

    Clin Toxicol (Phila)

    (2007)
  • R Butera et al.

    Diagnostic accuracy of urinary amanitin in suspected mushroom poisoning: a pilot study

    J Toxicol Clin Toxicol

    (2004)
  • U Mengs et al.

    Legalon® SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning

    Curr Pharm Biotechnol

    (2012)
  • K Letschert et al.

    Molecular characterization and inhibition of amanitin uptake into human hepatocytes

    Toxicol Sci

    (2006)
  • L Sorodoc et al.

    Is MARS system enough for A. phalloides-induced liver failure treatment

    Hum Exp Toxicol

    (2010)
  • K Hruby et al.

    Chemotherapy of Amanita phalloides poisoning with intravenous silibinin

    Hum Toxicol

    (1983)
  • LE Schmidt et al.

    Risk factors in the development of adverse reactions to N-acetylcysteine in patients with paracetamol poisoning

    Br J Clin Pharmacol

    (2001)
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