acute liver failure

 

Acute liver failure Straight to the point of care Last updated: May 29, 2020 Table of Contents Overview 3 Summary 3 Definition 3 Theory 4 Epidemiology 4 Aetiology 4 Pathophysiology 5 Classification 5 Case history 6 Diagnosis 7 Approach 7 History and exam 10 Risk factors 12 Investigations 15 Differentials 19 Criteria 20 Management 23 Approach 23 Treatment algorithm overview 25 Treatment algorithm 27 Emerging 34 Primary prevention 34 Secondary prevention 34 Patient discussions 35 Follow up 36 Monitoring 36 Complications 37 Prognosis 38 Guidelines 40 Diagnostic guidelines 40 Treatment guidelines 40 Online resources 42 References 43 Disclaimer 56 Acute liver failure Overview Summary Rare disease defined by jaundice, coagulopathy, and hepatic encephalopathy. The aetiology and the interval from onset of jaundice to the development of encephalopathy have a significant impact on prognosis. Aetiology is established by history, serological assays, and exclusion of alternative causes, including acute presentations of chronic liver diseases. Treatment involves intensive care unit monitoring, specific therapies based on aetiology, and management of known complications. All patients should be considered for possible liver transplantation. Prognostic models may be used to assess the probability of spontaneous recovery and are instrumental in selection of patients who should potentially undergo liver transplantation. Definition Acute liver failure (ALF) is a rapid decline in hepatic function characterised by jaundice, coagulopathy (INR >1.5), and hepatic encephalopathy in patients with no evidence of prior liver disease.[1] [2] [3] ALF may be classified as hyperacute, acute, or subacute, depending on the interval from the onset of jaundice to the development of encephalopathy.[4] The term acute liver failure is preferred over fulminant hepatic failure or acute hepatic necrosis, although these terms have been used historically to classify hepatic failure.[1] [2] [5] O V E R VIE W This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 3 Acute liver failure Theory T H E O R Y Epidemiology ALF is a rare event, with an incidence of approximately 2000 cases annually in the US.[7] ALF was responsible for 3.3% of US liver transplants in 2017.[8] Due to its rarity and acute presentation, ALF had not been well studied prospectively until the establishment of the US Acute Liver Failure Study Group (ALFSG). Over nearly 20 years, more than 2000 adult patients in over 30 US centres have been enrolled in the ALFSG database.[5] [9] [10] A separate database has also been established for paediatric ALF cases arising from 19 US, 1 Canadian, and 2 UK centres. Analysis of the adult dataset has revealed that the majority of cases were women (67%) and the mean age was 38 years (range 17-79 years). The overall rate of spontaneous recovery without liver transplantation was 45%; 25% of cases received a liver transplant; and the overall mortality rate was 30%.[5] These reported outcomes are an improvement over those described in past decades, partly due to changing trends in aetiologies of ALF. Additional data have revealed improvements in overall short-term survival, transplant-free survival, and post-transplant survival over the last decade in particular, possibly as a result of early recognition and changes in intensive care management.[10] Aetiology Identifying the cause of ALF is important to guide treatment and determine prognosis. Aetiology varies significantly between different parts of the world. In the UK and the US, paracetamol overdose is the most common aetiology of ALF. Analysis of 2614 adult patients prospectively enrolled in the US Acute Liver Failure Study Group (ALFSG) between 1998 and 2019 showed that paracetamol hepatotoxicity accounts for approximately 46% of all cases.[11] Paracetamol overdose accounts for nearly 66% of ALF cases in the UK.[12] Paracetamol overdose appears to be equally divided between intentional and unintentional cases.[13] Other causes of ALF include idiosyncratic drug-induced liver injury (11%), acute hepatitis B (7%), autoimmune hepatitis (7%), ischaemic hepatitis (7%), and acute hepatitis A (1%). Up to 12% of cases remain indeterminate.[11] Altogether, over half of all ALF cases are associated with a drug-induced reaction. After paracetamol, antimicrobials are the most commonly implicated drugs.[14] Studies suggest that paracetamol may potentially contribute to, or be a causal factor in, many cases that are otherwise indeterminate.[15] In cases of non-paracetamol drug-induced liver injury, reports have noted a rise in ALF resulting from complementary medicines and illicit compounds.[16] [14] A multicentre retrospective analysis conducted in Sweden (279 patients) showed a similar distribution of ALF aetiology for paracetamol toxicity-induced ALF (42%) and other drug-induced ALF (15%).[17] However, a smaller retrospective study conducted in Germany (102 patients) revealed a different distribution of ALF aetiologies with indeterminate cause for 21% of the cases, followed by acute hepatitis B (18%), paracetamol (16%), and Budd-Chiari syndrome (9%).[18] Although the retrospective studies from Sweden and Germany are insightful, the key advantage of the data reported from the ALFSG was the prospective design and size of the study compared with the Swedish and German cohorts. This adds to the validity of the findings from the ALFSG, although it is clear that aetiology may also depend on geography. 4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Theory Globally, viral infection accounts for the majority of cases of ALF. In Bangladesh and India, hepatitis E virus accounts for 75% and 44% of cases respectively. In Japan, 42% of cases are caused by hepatitis B virus (HBV). HBV accounts for 22% of cases in Sudan. Paracetamol overdose is very rare in all of these regions.[19] Pathophysiology Although ALF develops as a consequence of many different causal pathways, most cases are characterised by massive hepatocyte necrosis, which may ultimately result in organ failure. On a cellular level, both hepatocyte necrosis and apoptosis may coexist in the setting of ALF.[9] ALF can occur without histological evidence of hepatocellular necrosis; examples of this include acute fatty liver of pregnancy and Reye's syndrome.[20] Efforts to more accurately define factors involved in the pathogenesis of liver injury in the setting of ALF, including hepatocyte apoptosis and regeneration, may lead to the discovery of novel biomarkers that could predict outcomes.[9] ALF secondary to drug-induced liver injury may occur as an idiosyncratic drug reaction or, as in the case of paracetamol, in a dose-dependent manner. Paracetamol is predominantly metabolised in the liver through glucuronidation and sulfation, with a small amount metabolised by the cytochrome P450 system. A toxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI), generated via the P450 pathway is subsequently conjugated by glutathione. In the setting of paracetamol overdose, glutathione stores may become depleted, resulting in direct hepatocyte injury via NAPQI.[21] Induction of the P450 system through chronic alcohol use or barbiturates and depletion of glutathione stores in settings such as nutritional deficiency may result in a greater propensity to develop paracetamol hepatotoxicity. Classification By interval from onset of jaundice to development of hepatic encephalopathy[3] [4] Liver failure is classified as:[4] • Hyperacute if occurring within 7 days • Acute if occurring between 8 and 28 days • Subacute if occurring between 29 days and 12 weeks. A previous classification would consider liver failure also as:[3] • Fulminant if occurring within 2 weeks • Subfulminant if occurring between 2 and 12 weeks. By interval from onset of hepatic illness to development of hepatic encephalopathy[1] [2] Hepatic failure is classified as: T H E O R Y This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 5 Acute liver failure Theory T H E O R Y • Fulminant if occurring within 8 weeks[1] • Late-onset if occurring between 8 and 26 weeks.[2] Case history Case history #1 A 48-year-old woman with a history of migraine headaches presents to the emergency department with altered mental status over the last several hours. She was found by her husband, earlier in the day, to be acutely disorientated and increasingly somnolent. On physical examination, she has scleral icterus, mild right upper quadrant tenderness, and asterixis. Preliminary laboratory studies are notable for a serum alanine aminotransferase of 6498 units/L, total bilirubin of 95.8 micromol/L (5.6 mg/dL), and INR of 6.8. Her husband reports that she has consistently been taking pain medications and started taking additional 500 mg paracetamol pills several days ago for lower back pain. Further history reveals a medication list with multiple paracetamol-containing preparations. Other presentations The defining features of ALF are jaundice, coagulopathy (INR >1.5), and hepatic encephalopathy.[1] [2] [3] [4] Hepatic encephalopathy is generally preceded by the onset of jaundice. Patients may present with associated non-specific symptoms such as malaise, nausea, and abdominal pain. Hepatic encephalopathy in the setting of ALF may progress rapidly from mild disorientation and hypersomnolence to coma;[6] a rapid course to advanced encephalopathy is associated with an increased risk of cerebral oedema and intracranial hypertension. Although clinical jaundice is considered a defining feature of ALF, it may not always be present, particularly in hyperacute presentations. Complications of ALF, such as infection, renal failure, hypoglycaemia, acidosis, and shock, may be present at the time of presentation. 6 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Diagnosis Approach The diagnosis of ALF is established through a careful history, including: chronology of events prior to presentation; physical examination; laboratory studies. Early recognition, diagnosis, and establishment of prognosis are paramount to providing an optimal management strategy in patients with ALF. Once the diagnosis is made, early contact with a liver transplant centre should be addressed, as all patients with ALF should be considered for possible liver transplantation.[39] Urgent cadaveric liver transplantation is the standard of care for patients with ALF. History and physical findings ALF is defined by the onset of jaundice, coagulopathy (INR >1.5), and hepatic encephalopathy in patients with no prior history of liver disease.[1] [2] [3] Assessment for potential exposure risks, drug ingestions, alcohol, or substance abuse, and establishment of the time course of illness, are critical. Exposure to specific hepatotoxins, such as ingestion of Amanita phalloides mushrooms, may require specific management strategies and therapy. Age >40 years, female sex, poor nutritional status, pregnancy, chronic hepatitis B, and the use of multiple paracetamol preparations for chronic pain are also key risk factors to be considered. Assessment of the time course of the illness according to the interval from the onset of jaundice to the development of encephalopathy allows further classification of ALF into categories based on hyperacute (if occurring within 7 days), acute (between 8 and 28 days), or subacute presentations (between 29 days and 12 weeks).[4] Patients who present with a hyperacute time course are more likely to have a spontaneous resolution, but are also at greater risk of developing cerebral oedema and intracranial hypertension. The aetiology of ALF is not only established by history and serological assays, but also by the exclusion of alternative causes, including acute presentations of chronic liver diseases. Chronic liver diseases such as autoimmune hepatitis and chronic hepatitis B may present as an acute exacerbation with the clinical features of ALF. Abdominal pain, nausea, vomiting, and malaise are common symptoms, while right upper quadrant tenderness may present less frequently. Hepatomegaly may be present in the setting of acute viral hepatitis, congestive heart failure with hepatic congestion, Budd-Chiari syndrome, and infiltrative malignancies. Physical examination findings may provide clues that suggest the presence of an underlying chronic liver disease, such as splenomegaly, spider angiomata, palmar erythema, and ascites. Emphasis should be placed on determining the aetiology of ALF, as it is an important prognostic indicator and will guide further management with regards to aetiology-specific therapies. Clinical evaluation of hepatic encephalopathy Hepatic encephalopathy is one of the defining features of ALF. Hepatic encephalopathy encompasses a spectrum of neurological and psychiatrical changes, and initial symptoms may be subtle. The American Association for the Study of Liver Diseases and the European Association for the Study of the Liver guidelines advise using the West Haven Criteria to grade hepatic encephalopathy.[40] • Grade 1: subtly impaired awareness, sleep alterations, shortened attention span, impaired addition or subtraction, heightened mood or anxiety, oriented in time and space. DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 7 Acute liver failure Diagnosis DIA G N O SIS • Grade 2: lethargy or apathy, disorientation for time, obvious personality change, inappropriate behaviour, dyspraxia, asterixis. • Grade 3: somnolence to semi-stupor, responsive to vocal stimuli, marked confusion, gross disorientation (disoriented in time and space), bizarre behaviour. Physical findings may include hyper-reflexia, nystagmus, clonus, and rigidity. • Grade 4: coma. Encephalopathy grade at the time of presentation is an important factor linked to prognosis. In addition, subsequent changes in severity of hepatic encephalopathy play a role in management decisions during the course of hospitalisation for ALF, as advanced grades (3 to 4) are associated with severe complications such as cerebral oedema and intracranial hypertension. A careful physical assessment is an important component of the initial evaluation. This should include a neurological examination to characterise the degree of hepatic encephalopathy, particularly in cases with increased severity, to assess for evidence of intracranial hypertension. The examination should include an assessment of the patient’s orientation in time and space. Patients with grade 2 hepatic encephalopathy are disorientated in time, and patients with grade 3 hepatic encephalopathy are disorientated in time and space.[40] Patients may demonstrate asterixis, a flapping movement of the hands that is elicited by extending the arms, dorsiflexing the wrist, and spreading the fingers. It is a form of negative myoclonus, where a brief loss of tone in agonist muscles is followed by a compensatory jerk in antagonist muscles.[41] Patients may develop motor signs such as hypertonia, hyper-reflexia, and a positive Babinski's sign. Extra-pyramidal signs such as bradykinesia, slow monotonous speech, and dyskinesia are common.[40] Physical exam findings associated with cerebral oedema and intracranial hypertension include abnormal pupillary reflexes, muscular rigidity, and decerebrate posturing in advanced stages. A more specialised diagnostic assessment may be performed based on suspicion of specific causes of ALF, as in the case of a slit-lamp ophthalmological examination to assess for Kayser-Fleischer rings in acute Wilson's disease. Tests The aetiology of ALF is primarily established by history, serological assays, laboratory studies, and imaging. Initial laboratory studies not only provide valuable prognostic information, but also identify early development of complications associated with ALF. Initial diagnostic tests should include: • Blood tests: prothrombin time and international normalised ratio (INR) and liver function tests, viral serologies, autoimmune markers, toxicology screening, and parameters to assess overall clinical status, such as haematology, acid-base balance, and renal dysfunction. • All at-risk female patients of childbearing age should have a pregnancy test. • Paracetamol levels can be useful when elevated; however, low paracetamol levels do not rule out paracetamol hepatotoxicity, and suspected cases should be managed accordingly. Over 50% of patients with acute liver injury or ALF attributed to paracetamol may have undetectable levels of plasma paracetamol levels.[42] 8 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Diagnosis • Initial imaging should include a chest x-ray to confirm possible aspiration pneumonia or to rule out other pulmonary abnormalities, and abdominal Doppler imaging to assess hepatic vein thrombosis associated with Budd-Chiari syndrome. Additional diagnostic tests may include: • Polymerase chain reaction studies for hepatitis B, hepatitis C, and herpes simplex virus DFNA may establish the diagnosis before serology studies become positive. • HIV test. • Serum ceruloplasmin, serum and hepatic copper levels, 24-hour urinary copper excretion, and slitlamp ophthalmological evaluation for the presence of Kayser-Fleischer rings if Wilson's disease is suspected.[6] • Coombs test: in the presence of haemolysis, a negative Coombs test may further differentiate between Wilson's disease and autoimmune haemolysis, which is typically Coombs-positive. • Arterial ammonia levels are characteristically elevated if hepatic encephalopathy is present, although it is a non-specific test. High levels may predict an increased risk of developing intracranial hypertension. • Head computed tomography is useful for further evaluation of cerebral oedema or other underlying pathology in advanced encephalopathy. • Surveillance cultures: blood, urine, and sputum cultures should be obtained at regular intervals once advanced grade of encephalopathy develops. • Urinalysis and urine sodium should be obtained if renal dysfunction is present. • Liver biopsy: although a liver biopsy may provide additional information to suggest potential aetiologies of ALF in indeterminate cases, it is not a required test to confirm a diagnosis and generally does not have an impact on clinical management, outcome, or assessment of prognosis. For these reasons, liver biopsies in the setting of ALF are not usually performed.[43] An exception to this may include circumstances in which there is suspicion for infiltrative malignancy such as lymphoma or metastatic liver disease.[44] A liver biopsy may also be helpful in the diagnosis of conditions such as suspected autoimmune hepatitis or acute herpes simplex virus hepatitis.[45] [46] If a liver biopsy is considered, a transjugular approach is preferable given the increased risk of bleeding associated with coagulopathy during ALF. Type and screen of blood units should be performed in case a transfusion is needed. Prognosis assessment Based on the clinical findings on presentation, initial laboratory studies, and aetiology of ALF, an assessment can be made regarding the severity and prognosis associated with a course of ALF. Aetiology is a key factor in the assessment of prognosis. Paracetamol hepatotoxicity is more commonly associated with a hyperacute presentation and a higher rate of spontaneous recovery in contrast with idiosyncratic drug reactions, which may follow a subacute course and have a less favourable prognosis.[4] [11] Acute hepatitis A and ischaemic hepatitis also have a relatively favourable prognosis. Acute hepatitis B, autoimmune hepatitis, Wilson's disease, Budd-Chiari syndrome, and indeterminate causes indicate a poorer prognosis.[6] DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 9 Acute liver failure Diagnosis DIA G N O SIS Grade 3 or 4 hepatic encephalopathy on admission to hospital indicates a poorer prognosis. Laboratory studies including INR, bilirubin, creatinine, and negative logarithm of hydrogen ion activity are components of prognostic tools such as the King’s College Criteria. A low-factor V level in the presence of hepatic encephalopathy may be predictive of mortality, particularly in patients with ALF secondary to viral hepatitis.[47] Several prognostic criteria have been proposed and validated in the setting of ALF. These criteria can be instrumental in identifying patients at high risk of mortality. The most widely accepted prognostic tool is the King’s College Criteria.[48] Overall, these criteria are instrumental in selecting patients who have a high risk of mortality with ALF. However, they have limitations, and reliance upon prognostic scoring systems to determine candidacy for liver transplantation is not recommended by the American Association for the Study of Liver Diseases.[6] History and exam Key diagnostic factors presence of risk factors (common) • Key risk factors include alcohol abuse, age >40 years, female gender, poor nutritional status, pregnancy, chronic hepatitis B, and the use of multiple paracetamol preparations for chronic pain. hepatotoxic medication (common) • Determining whether ALF is associated with paracetamol overdose or other hepatotoxic medications is important in assessment of prognosis and initiation of aetiology-specific therapies such as acetylcysteine. • Patients with chronic pain who use multiple analgesics, particularly narcotics, are at potentially increased risk of ALF as they may be taking multiple paracetamol-containing preparations.[22] Most cases of paracetamol-induced ALF in the US involve overdose with paracetamol combination products, including paracetamol combined with an opioid and paracetamol combined with diphenhydramine.[49] Although only approximately 10% of drug-induced liver injury cases progress to ALF, this is associated with a poor prognosis, high mortality, and need for liver transplantation in up to 40% of patients.[50] jaundice (common) • A defining feature of ALF. The presence of jaundice and its relation to the onset of hepatic encephalopathy is important in the assessment of prognosis and further characterisation of ALF.[1] [2] [3] [4] signs of hepatic encephalopathy (common) • A defining feature of ALF. Hepatic encephalopathy encompasses a spectrum of neurological and psychiatrical symptoms and signs. The time of onset of encephalopathy in relation to jaundice is important in the assessment of prognosis and further characterisation of ALF.[1] [2] [3] [4] • Assessment of a patient's level of consciousness, as well as physical examination findings such as asterixis, is essential. The West Haven Criteria may be used to categorise hepatic encephalopathy into grades based on severity.[51] [52] [40] 10 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Diagnosis • Grade 1: subtly impaired awareness, sleep alterations, shortened attention span, impaired addition or subtraction, heightened mood or anxiety, oriented in time and space. • Grade 2: lethargy or apathy, disorientation for time, obvious personality change, inappropriate behaviour, dyspraxia, asterixis. • Grade 3: somnolence to semi-stupor, responsive to vocal stimuli, marked confusion, gross disorientation (disoriented in time and space), bizarre behaviour. Physical findings may include hyperreflexia, nystagmus, clonus, and rigidity. • Grade 4: coma. Other diagnostic factors absence of history of chronic liver disease (common) • Chronic liver disease may present as an acute exacerbation with the clinical features of ALF. In addition, patients with chronic liver disease may be at increased risk of liver failure secondary to drug toxicities or superinfections with other forms of viral hepatitis.[35] [36] [37] [33] The presence of underlying chronic liver disease generally precludes the diagnosis of ALF, as ALF is defined by the absence of pre-existing liver disease. abdominal pain (common) • Common symptom in ALF. nausea (common) • Common symptom in ALF. vomiting (common) • Common symptom in ALF. malaise (common) • Common symptom in ALF. signs of cerebral oedema (common) • Cerebral oedema is a common complication of ALF with increased frequency in advanced grades of hepatic encephalopathy and hyperacute presentations. Physical examination findings associated with cerebral oedema and intracranial hypertension include abnormal pupillary reflexes, muscular rigidity, and decerebrate posturing in advanced stages. right upper quadrant tenderness (common) • May be present in ALF. hepatomegaly (common) • May be present in settings such as acute viral hepatitis, congestive heart failure with hepatic congestion, Budd-Chiari syndrome, and infiltrative malignancies. absence of splenomegaly (common) • The presence of this finding may suggest chronic liver disease or underlying cirrhosis. absence of spider angiomata (common) • The presence of this finding may suggest chronic liver disease or underlying cirrhosis. DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 11 Acute liver failure Diagnosis DIA G N O SIS absence of palmar erythema (common) • The presence of this finding may suggest chronic liver disease or underlying cirrhosis. absence of ascites (common) • The presence of this finding may suggest chronic liver disease or underlying cirrhosis. depression or suicidal ideation (common) • In the US, approximately one half of ALF cases secondary to paracetamol overdose are intentional and over half of cases occur in individuals who are taking antidepressant therapy.[22] Patients who have a history of repeated suicide attempts may potentially not be eligible for liver transplant listing.[39] • Methods to restrict access to paracetamol have been used in Europe with significant reductions of hospital admissions, liver transplants, and deaths associated with paracetamol overdose.[53] exposure to hepatotoxins (uncommon) • Exposure to specific hepatotoxins, such as ingestion of Amanita phalloides mushrooms, may require specific management strategies and therapy. Understanding these potential exposure risks in a particular case of ALF allows the clinician to proceed with specific therapies promptly. illicit drug abuse and high-risk behaviours (uncommon) • Certain populations such as intravenous drug users are at increased risk of exposure to viral hepatitis, such as hepatitis B or C, which may be causal or contribute to a presentation of ALF. Risk factors Strong chronic alcohol abuse • A significant risk factor for the development of ALF. Alcohol use is more commonly associated with unintentional paracetamol overdoses and may be a risk factor for significant hepatotoxicity in patients who present with paracetamol overdose.[22] [23] Alcohol abusers have been shown to develop ALF following ingestion of lower doses of paracetamol (≤4 g per day) and have lower serum paracetamol levels than non-abusers.[22] In addition, alcohol abuse may be associated with a greater risk of developing ALF in the setting of acute exposure to a hepatitis virus, such as hepatitis B.[24] poor nutritional status • Associated with an increased risk of ALF in the setting of paracetamol hepatotoxicity due to depletion of hepatic glutathione stores, and may be a contributing factor to the increased risk of ALF in alcoholics following paracetamol overdose. • May also be a risk factor for ALF in the setting of acute viral hepatitis.[24] female sex • Several prospective studies have found that women are more likely to develop ALF,[5] particularly in the setting of drug-induced liver injury.[25] [14] 12 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Diagnosis age >40 years • In a prospective cohort of individuals with paracetamol-induced ALF, increased age was shown to be associated with a higher incidence of unintentional paracetamol overdose and ALF in older patients occurred with lower doses of ingested paracetamol (≤4 g per day).[22] • Large retrospective studies have found that age >40 years may be associated with an increased risk of significant hepatotoxicity, ALF, and mortality in patients who present with paracetamol overdose.[23] [26] • Prospective studies have also determined that increasing age may be associated with the development of ALF in cohorts presenting with predominantly acute viral hepatitis.[27] pregnancy • The risk of ALF is increased in the setting of acute viral hepatitis and pregnancy, particularly hepatitis E infection.[28] Data suggest that hepatitis E may occur more frequently in developed countries than previously thought, and is associated with a significant risk during pregnancy.[29] The incidence of hepatitis E infection is increased among pregnant women and is associated with a higher hepatitis E viral load, increased risk of ALF, and increased mortality.[30] The incidence of ALF in pregnant women with acute hepatitis E infection has been reported as high as 69% in some populations.[30] • Acute fatty liver of pregnancy, and the haemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome, occur during pregnancy and may present as ALF. chronic hepatitis B • Hepatitis B surface antigen carriers are up to 9 times more likely to develop ALF in the setting of acute hepatitis, regardless of aetiology.[31] [32] • Individuals with chronic hepatitis B infection are also at risk of developing co-infection with hepatitis D virus, which is associated with a greater frequency of severe hepatitis and ALF compared with hepatitis B alone.[33] Hepatitis B carriers who undergo immunosuppressive or cancer chemotherapy can develop viral re-activation and ALF.[34] chronic pain and narcotic use • Patients with chronic pain who use multiple analgesics, particularly narcotics, are at potentially increased risk of ALF as they may be taking multiple paracetamol-containing preparations.[22] complementary and alternative medicine hepatotoxicity • The incidence of ALF resulting from complementary and alternative medicines has increased over the last decade and is associated with higher rates of liver transplantation and lower transplant-free survival compared with ALF secondary to prescription medicine drug-induced liver injury.[16] [14] Weak paracetamol and antidepressant therapy • In a prospective series of patients, included in the US Acute Liver Failure Study Group, who developed paracetamol-induced ALF, the majority (61%) of individuals were on antidepressant therapy.[22] chronic hepatitis C • In one retrospective study of patients presenting with paracetamol overdose, chronic hepatitis C infection was associated with an increased risk of acute liver injury and a more severe disease course, including liver failure.[35] DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 13 Acute liver failure Diagnosis DIA G N O SIS • Patients with chronic hepatitis C appear also to have a significantly greater risk of developing ALF in the setting of acute hepatitis A superinfection compared with patients with chronic hepatitis B.[36] HIV and hepatitis C co-infection • One large retrospective study found that individuals with HIV infection have an overall greater risk of ALF when they are co-infected with hepatitis C. This risk may be increased as much as 4-fold in the setting of highly active antiretroviral therapy, although these cases involve patients with underlying chronic hepatitis C infection and likely pre-existing chronic liver disease.[37] 14 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Diagnosis Investigations 1st test to order Test Result liver function tests • Hyperbilirubinaemia is associated with jaundice, a defining feature of ALF.[1] [2] [3] [4] Elevations in liver enzymes are variable depending on aetiology. Paracetamol hepatotoxicity is associated with very high aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. In other forms of drug-induced liver injury, a ratio of the fold-increase of ALT or AST over the upper limit of normal, to the foldincrease of alkaline phosphatase over the upper limit of normal that is >5 has a 90% sensitivity for ALF.[54] • Wilson's disease typically presents with an alkaline phosphatase:bilirubin ratio of <4 and AST: ALT ratio >2.2. In one prospective cohort, these combined laboratory features had a sensitivity and specificity of 100% in the diagnosis of ALF secondary to Wilson's disease.[55] hyperbilirubinaemia, elevated liver enzymes prothrombin time/INR • The presence of coagulopathy (INR >1.5) is a defining feature of ALF.[1] [2] [3] [4] elevated INR (>1.5) basic metabolic panel • Renal failure is a known complication of ALF and is predictive of mortality, particularly in paracetamol overdose.[56] Metabolic derangements in potassium, phosphate, and magnesium are common and should be corrected promptly. elevated urea and creatinine, metabolic derangements FBC • The presence of leukocytosis may suggest infection. Anaemia may be present in some patients, particularly in the setting of ALF associated with Wilson's disease in which Coombs-negative haemolytic anaemia may occur. Thrombocytopenia may suggest preexisting advanced liver disease. A decline in platelets within 7 days of presentation may be associated with onset of systemic inflammatory response syndrome and risk of multi-organ system failure.[57] leukocytosis, anaemia, thrombocytopenia blood type and screen • Done pre-emptively in case a blood transfusion is required specific blood profile of patient arterial blood gas • The presence of acidosis is an important prognostic indicator, particularly in paracetamol overdose.[56] metabolic acidosis arterial blood lactate • Important prognostic indicator in paracetamol-associated ALF, in which levels >3.5 mmol/L on presentation and >3.0 mmol/L following fluid resuscitation are predictive of mortality. The addition of arterial blood lactate to the King's College Criteria below may improve sensitivity in the prediction of mortality associated with paracetamolinduced ALF.[58] • ALF secondary to paracetamol overdose: pH <7.30, or presence of all 3 of the following: INR >6.5, serum creatinine >300 micromol/L (>3.4 mg/dL), and grade 3 or 4 hepatic encephalopathy. elevated DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 15 Acute liver failure Diagnosis DIA G N O SIS Test Result • Non-paracetamol-associated ALF: INR >6.5 (PT >100 seconds) or presence of any 3 of the following: age between 10 and 40 years; aetiology non-A, non-B hepatitis, or idiosyncratic drug reaction; duration of jaundice before hepatic encephalopathy >7 days; INR >3.5 (PT >50 seconds); serum bilirubin >300 micromol/L (>17.6 mg/ dL). paracetamol level • Acetylcysteine therapy should be administered in all suspected cases of paracetamol overdose, regardless of the dose or timing of paracetamol ingestion.[59] [42] may be elevated; however, low paracetamol levels do not exclude paracetamol hepatotoxicity urine toxicology screen • May be helpful to determine paracetamol levels in urine following a paracetamol overdose. may be positive for paracetamol factor V level • A low result in the presence of hepatic encephalopathy may be predictive of mortality, particularly in patients with ALF secondary to viral hepatitis.[60] low (<20% to 30% of normal) viral hepatitis serologies • Include antihepatitis A immunoglobulin (Ig)M, antihepatitis B core IgM, hepatitis B surface antigen, antihepatitis C IgG, and antihepatitis E IgM. Helpful in exploring potential aetiologies of ALF and may guide management, particularly in acute hepatitis B in which antiviral therapy may be initiated. may be positive autoimmune hepatitis markers • Serological markers including antinuclear antibody, anti-smoothmuscle antibody, and quantitative immunoglobulins can help to establish this diagnosis and guide further management. may be positive pregnancy test • A serum beta-human chorionic gonadotrophin (hCG) should be obtained in all females of childbearing age presenting with ALF. Acute viral hepatitis, acute fatty liver of pregnancy, and the haemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome may occur during pregnancy. may be positive chest x-ray • To assess for findings such as aspiration pneumonia (many patients present obtunded with hepatic encephalopathy), pulmonary oedema, or other abnormalities that require further evaluation or treatment. possible aspiration pneumonia abdominal ultrasound with Doppler • An abdominal Doppler study may assess vessel patency and evidence of hepatic vein thrombosis associated with Budd-Chiari syndrome. Abdominal sonography may reveal hepatic surface nodularity suspicious for pre-existing cirrhosis; however, this finding may actually reflect acute large-scale necrosis and parenchymal collapse with foci of regenerative nodules rather than chronic changes associated with chronic liver disease.[61] hepatic vessel thrombosis, loss of hepatic venous signal and reverse flow in the portal vein in Budd-Chiari syndrome; hepatomegaly, splenomegaly, hepatic surface nodularity 16 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Diagnosis Other tests to consider Test Result viral hepatitis polymerase chain reaction (PCR) studies • Include hepatitis B virus DNA, herpes simplex virus DNA, and hepatitis C virus RNA. May assist in establishing the diagnosis, particularly in the acute setting, when serologies may be negative. Obtaining additional viral serologies or PCR studies for Epstein-Barr virus, cytomegalovirus, Varicella zoster , and adenovirus may also be considered as these can be associated with ALF. may be positive when serology is negative serum ceruloplasmin • Probably low in ALF secondary to Wilson's disease; however, this is a non-specific finding. If Wilson's disease is suspected, further work-up should include an assessment for alkaline phosphatase:total bilirubin ratio <4, aspartate aminotransferase:alanine aminotransferase ratio >2.2, serum copper level, 24-hour urine collection for quantitative copper, slit-lamp ophthalmological evaluation for the presence of Kayser-Fleischer rings, and hepatic copper levels if a liver biopsy is performed.[55] [62] low (<50 mg/L [<5 mg/dL]) in Wilson's disease serum copper • If Wilson's disease is suspected, further work-up should include an assessment for alkaline phosphatase:total bilirubin ratio <4, aspartate aminotransferase:alanine aminotransferase ratio >2.2, ceruloplasmin, 24-hour urine collection for quantitative copper, slit-lamp ophthalmological evaluation for the presence of KayserFleischer rings, and hepatic copper levels if a liver biopsy is performed.[55] [62] elevated (>31 micromol/L [>200 micrograms/dL]) in Wilson's disease 24-hour urinary copper excretion • Usually very elevated in the setting of ALF secondary to Wilson's disease, with levels >125 micrograms over 24 hours. If Wilson's disease is suspected, further work-up should include an assessment for alkaline phosphatase:total bilirubin ratio <4, aspartate aminotransferase:alanine aminotransferase ratio >2.2, ceruloplasmin, serum copper level, slit-lamp ophthalmological examination for the presence of Kayser-Fleischer rings, and hepatic copper levels if a liver biopsy is performed.[55] [62] elevated (>100 micrograms/24 hours) in Wilson's disease slit-lamp ophthalmological examination • If Wilson's disease is suspected, a slit-lamp examination for the presence of Kayser-Fleischer rings may be performed. However, this finding may be absent in 50% of patients with Wilson's disease. Further work-up may include an assessment for alkaline phosphatase:total bilirubin ratio <4, aspartate aminotransferase:alanine aminotransferase ratio >2.2, ceruloplasmin, serum copper level, 24-hour urine collection for quantitative copper, and hepatic copper levels if a liver biopsy is performed.[55] [62] positive (Kayser-Fleischer rings present) in Wilson's disease arterial ammonia • Characteristically elevated if hepatic encephalopathy is present. This may be useful when differentiating between other causes of altered mental status; however, it is a non-specific test. High ammonia levels to >200 micromol/L are more specific and may predict an increased risk of developing intracranial hypertension.[63] elevated DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 17 Acute liver failure Diagnosis DIA G N O SIS Test Result HIV test • Risk of ALF is increased in patients with HIV and hepatitis C coinfection. may be positive urinalysis and urine sodium • Should be obtained if renal dysfunction is present. Aetiologies of renal failure in ALF may include hypovolaemia, acute tubular necrosis, and hepatorenal syndrome. proteinuria, sediment, low urine sodium (<10 mEq/L) surveillance cultures • Blood, urine, and sputum cultures should be obtained at regular intervals once advanced grade of encephalopathy develops. may be positive Coombs test • If haemolysis is present, a Coombs test may further differentiate between Wilson's disease, which is associated with a Coombsnegative haemolysis, versus autoimmune haemolysis, which is typically Coombs-positive. positive or negative liver biopsy • The transjugular approach is preferred given the potential bleeding risk associated with coagulopathy during ALF. In addition to a general histopathological evaluation, attention should be given to assess for the presence of viral inclusions that may suggest acute herpes simplex hepatitis, hepatic copper levels if Wilson's disease is suspected, and for features suggestive of autoimmune hepatitis. Liver biopsies are rarely performed in the setting of ALF because they are not required to confirm a diagnosis and generally do not have an impact on clinical management or prognosis. hepatocellular necrosis, microvesicular steatosis, viral inclusions, elevated hepatic copper CT scan of head • Should be considered once grade 3 to 4 hepatic encephalopathy develops to assess for presence of cerebral oedema or other underlying pathology. cerebral oedema, haemorrhage 18 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Diagnosis Differentials Condition Differentiating signs / symptoms Differentiating tests Severe acute hepatitis • Patients may present with jaundice and coagulopathy. However, this would not be considered ALF in the absence of hepatic encephalopathy. Severe acute hepatitis should be followed very closely as this may potentially develop into ALF or subacute liver failure, depending on the time course and development of hepatic encephalopathy. • Absence of hepatic encephalopathy. According to the West Haven Criteria, hepatic encephalopathy can be categorised into 4 grades based on severity:[51] [52] [40] • Grade 1: subtly impaired awareness, sleep alterations, shortened attention span, impaired addition or subtraction, heightened mood or anxiety, oriented in time and space. • Grade 2: lethargy or apathy, disorientation for time, obvious personality change, inappropriate behaviour, dyspraxia, asterixis. • Grade 3: somnolence to semi-stupor, responsive to vocal stimuli, marked confusion, gross disorientation (disoriented in time and space), bizarre behaviour. Physical findings may include hyper-reflexia, nystagmus, clonus, and rigidity. • Grade 4: coma. Cholestasis • Jaundice may result from intra- or extrahepatic biliary obstruction as well as from intrahepatic cholestasis due to conditions such as drug-induced liver injury or a chronic cholestatic liver disease. In the setting of an acute biliary obstruction, a patient may present with shock associated with cholangitis. Key features that distinguish these presentations from ALF include absence of coagulopathy and of hepatic encephalopathy, both of which are present during ALF. • Normal prothrombin time (PT)/INR, absence of hepatic encephalopathy (according to the West Haven Criteria as mentioned above).[51] [52] [40] In the presence of coagulopathy associated with cholestatic disorders and vitamin K deficiency, administration of subcutaneous vitamin K would improve PT/INR and may also be considered as a differentiating test. DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 19 Acute liver failure Diagnosis DIA G N O SIS Condition Differentiating signs / symptoms Differentiating tests Haemolysis • May present with jaundice characterised by an elevated unconjugated (indirect) serum bilirubin. • Typically occurs in the absence of liver dysfunction; therefore, coagulopathy and hepatic encephalopathy would not be present. Exceptions to this include ALF secondary to Wilson's disease, which may be associated with a Coombsnegative haemolytic anaemia.[62] ALF secondary to autoimmune hepatitis may coincide with an acute autoimmune haemolytic anaemia.[64] Sickle cell disease may also present acutely with jaundice, haemolysis, and liver dysfunction as a result of a sickle cell hepatopathy.[65] • Normal prothrombin time/ INR, abnormal peripheral blood smear, positive Coombs test, absence of hepatic encephalopathy (according to the West Haven Criteria as mentioned above).[51] [52] [40] Criteria King's College Criteria[56] The most widely accepted prognostic tool for patients who present with ALF. They were developed through a retrospective analysis of 588 consecutive patients with ALF who were admitted to the King's College Hospital Liver Unit between 1973 and 1987.[56] Prognostic factors associated with mortality were identified and assessed for predictive value. Note that the international normalised ratio (INR) level used in this prognostic tool differs from the INR level used as a diagnostic feature of ALF. Although fulfilment of these criteria has a high specificity for mortality, the sensitivity and negative predictive value remain low. Therefore, not fulfilling the criteria does not ensure survival.[66] [67] [68] [69] [70] The King’s College Criteria has a sensitivity of 68% to 69% and a specificity of 82% to 92%.[6] Although the King’s College Criteria have been validated in adult cohorts with ALF, data suggest they may not reliably predict outcomes in the paediatric population.[71] Overall, these criteria are instrumental in selecting patients who have a high risk of mortality with ALF. However, they have limitations, and reliance upon prognostic scoring systems to determine candidacy for liver transplantation is not recommended by the American Association for the Study of Liver Diseases.[6] ALF secondary to paracetamol overdose: • pH <7.30 or • INR >6.5 (PT >100 seconds) and serum creatinine >300 micromol/L (>3.4 mg/dL) in patients with grade 3 or 4 hepatic encephalopathy. Non-paracetamol associated ALF: 20 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Diagnosis • INR >6.5 (PT >100 seconds), or • any 3 of the following: age <10 or >40 years; aetiology non-A, non-B hepatitis, or idiosyncratic drug reaction; duration of jaundice before hepatic encephalopathy >7 days; INR >3.5 (PT >50 seconds); serum bilirubin >300 micromol/L (>17.6 mg/dL). Clichy criteria[60] Based on a French prospective study of patients presenting with acute viral hepatitis, in which patients identified as having the lowest survival without liver transplantation included those with hepatic encephalopathy and low factor V levels.[60] These criteria predicted mortality with a positive predictive value of 82% and negative predictive value of 98% in this cohort. However, subsequent studies have reported much lower predictive values which were inferior to the King's College Criteria in other populations, including paracetamol and non-paracetamol ALF.[66] [72] Presence of hepatic encephalopathy and factor V level: • <20% of normal in patients <30 years of age, or • <30% of normal in patients >30 years of age. Model for End-Stage Liver Disease (MELD)[73] [74] Adopted by the United Network for Organ Sharing and the Organ Procurement and Transplantation Network organization, the MELD score is well established as a validated predictive model of short-term mortality in patients with cirrhosis and is currently utilised in the allocation of donor organs in patients awaiting liver transplantation in the US.[73] [74] Several retrospective studies have reported the MELD score to have similar predictive value to the King's College Criteria for mortality associated with ALF.[75] [76] [77] [78] Prospective data from the US Acute Liver Failure Study Group revealed that a MELD score ≥30 in patients with paracetamol overdose had a high negative predictive value of 82%, such that patients with MELD scores <30 had a high probability of survival. In non-paracetamol ALF, a MELD score ≥30 had a positive predictive value of 81%, yet these values were not more accurate than the King's College Criteria.[6] [79] Based on findings from a large meta-analysis, the MELD score could have a role in predicting hospital mortality, particularly in non-paracetamol ALF.[80] • Laboratory studies required for the model: creatinine, total bilirubin, and INR. • MELD =9.57×log^e(creatinine)+3.78×log^e(bilirubin)+11.2× log^e(INR)+6.43 Acute Physiology and Chronic Health Evaluation (APACHE) II[81] The APACHE II scoring system was developed to predict mortality in patients of all disease categories admitted to intensive care units. The score comprises 12 common physiological and laboratory parameters, adjusted for patient age and underlying chronic health problems.[81] One prospective study in patients with paracetamol overdose found that an APACHE II score >15 was associated with high mortality and provided similar predictive value to the King's College Criteria, while another study found a score of ≥20 to be more predictive of mortality and need for liver transplant.[22] [82] Acute Liver Failure Study Group (ALFSG) Index[83] [84] A prognostic index was developed utilising a cohort of 250 patients enrolled in the ALFSG, and then validated in a separate cohort of 250 patients. Variables at the time of initial presentation that were found to have a strong association with mortality or need for liver transplantation included advanced coma grade, bilirubin, INR, elevated phosphorus, and serum levels of M30 antigen, a marker of apoptotic hepatocyte cell death. This index was found to have an overall sensitivity of 85.6% and specificity of 64.7% with no significant difference in performance between paracetamol and non-paracetamol ALF. Although this predictive index was superior to the King’s College Criteria and the MELD score, assessment of M30 antigen DIA G N O SIS This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 21 Acute liver failure Diagnosis DIA G N O SIS requires an enzyme-linked immunosorbent assay (ELISA)-based test and may not be readily available at most centres.[83] An additional model predictive of transplant-free survival was developed from the ALFSG database, involving 878 patients, and was then validated in a cohort of 885 patients. Variables predictive of transplant-free survival included the degree of hepatic encephalopathy, aetiology of ALF, requirement for vasopressors, bilirubin, and INR. Aetiologies of ALF considered to be favourable in this model included paracetamol (acetaminophen) overdose, pregnancy, ischaemia, or hepatitis A. The model performed with a sensitivity of 37% and specificity of 95% in determining an 80% transplant-free survival within the validation cohort.[84] 22 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Management Approach Early recognition and diagnosis are key factors in establishing a plan for optimal management of ALF. A careful history and a detailed clinical assessment are critical to discovering the potential aetiology of ALF. Aetiology-specific therapies should be initiated early, and intensive care monitoring is mandatory once hepatic encephalopathy is present. All patients with ALF should be considered for possible liver transplantation, and measures to transport patients to a liver transplant centre should be explored early during the hospital course.[39] [85] Intensive care management Patients with ALF should be admitted to an intensive care unit (ICU) once hepatic encephalopathy is present. The natural history of ALF may be characterised by a rapid deterioration in neurological status and there is a high risk of complications including sepsis and cerebral oedema, haemodynamic instability, and renal failure. ICU monitoring is critical in providing optimal care of the patient and to prevent and treat known complications of ALF. Neurological status should be monitored carefully and regularly for the development of grade 3 to 4 hepatic encephalopathy, which is associated with a greater risk of cerebral oedema and intracranial hypertension. • Grade 1: subtly impaired awareness, sleep alterations, shortened attention span, impaired addition or subtraction, heightened mood or anxiety, oriented in time and space. • Grade 2: lethargy or apathy, disorientation for time, obvious personality change, inappropriate behaviour, dyspraxia, asterixis. • Grade 3: somnolence to semi-stupor, responsive to vocal stimuli, marked confusion, gross disorientation (disoriented in time and space), bizarre behaviour. Physical findings may include hyper-reflexia, nystagmus, clonus, and rigidity. • Grade 4: coma. Efforts should be made to minimise elevations of intracranial pressure in patients with encephalopathy. The head of the patient's bed should be raised to approximately 30 degrees and surrounding stimuli reduced to a minimum.[85] Once advanced encephalopathy develops, tracheal intubation should be performed for airway protection. Propofol and fentanyl are preferred agents for analgesia and sedation due to their short half-lives. Intravenous fluids should be administered with caution to prevent volume depletion or overload; central venous pressure and pulmonary arterial monitoring as well as renal replacement therapy should be considered early to ensure optimal fluid management, particularly if there is evidence of renal or circulatory dysfunction.[6] [59] Enteral nutrition is generally a concern in the setting of encephalopathy, in which the patient is unable to obtain adequate nutrition due to an altered mental status. Therefore, enteral nutritional support with calorie-dense feeds should also be initiated early during the hospital course. Blood glucose levels should be monitored every 1 to 2 hours by finger stick to assess for hypoglycaemia. Hypoglycaemia should be corrected with intravenous glucose infusion, with a glycaemic target of 140 mg/ dl. Serum electrolytes, including sodium, phosphate, potassium, and magnesium, should be monitored at least twice daily and corrected aggressively. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 23 Acute liver failure Management M A N A G E M E N T Other routine laboratory studies such as coagulation activity, blood cell counts, and liver enzymes should also be monitored closely at regular intervals. Surveillance cultures from blood, urine, and sputum should be obtained periodically given the high risk of bacterial and fungal infection. The use of prophylactic antimicrobials has not been shown to affect clinical outcome.[6] [89] Proton-pump inhibitors or H2 antagonists are administered as prophylaxis for gastrointestinal bleeding.[6] Lactulose and rifaximin are not used in the treatment of hepatic encephalopathy in ALF.[85] Paracetamol overdose or mild to moderate (grade 1 or 2) encephalopathy Paracetamol overdose is the most common cause of ALF in the US and Western Europe.[5] Determination of whether paracetamol is responsible for ALF in an individual case is the most important factor to be addressed upon presentation.[90] Paracetamol overdose is associated with depletion of hepatic glutathione stores and accumulation of a toxic intermediate, N-acetyl-p-benzoquinone imine, leading to direct hepatocyte injury. Restoration of glutathione synthesis within hepatocytes is dependent on cysteine, which may be administered in the form of acetylcysteine.[21] Acetylcysteine therapy should be given in all cases of paracetamol overdose regardless of the dose or timing of paracetamol ingestion. Acetylcysteine therapy should continue until end points such as improvement of hepatic function by clinical and laboratory parameters have been achieved.[21] [59] One prospective placebo-controlled randomised clinical trial in patients with non-paracetamol ALF reported a significant survival benefit in patients with grade 1 or 2 hepatic encephalopathy who received acetylcysteine versus placebo.[91] Consequently, acetylcysteine therapy is recommended for ALF patients with mild to moderate hepatic encephalopathy, even in the absence of paracetamol ingestion.[90] Acetylcysteine may improve outcomes in non-paracetamol ALF through mechanisms involving a reduction in expression of pro-inflammatory cytokines, such as IL-17, and decreased hepatocyte necrosis.[92] [93] Other disease-specific therapies These should be considered once the aetiology of ALF has been established.[59] [6] Some potential aetiologies of ALF have specific therapies that may have an impact on clinical outcomes, including intravenous acyclovir for herpes simplex hepatitis and expedient delivery of the fetus in acute fatty liver of pregnancy or the haemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome. In cases of suspected Amanita phalloides mushroom poisoning, gastric lavage, activated charcoal, intravenous fluid resuscitation, intravenous penicillin-G, and acetylcysteine should be given. Silymarin (milk thistle) therapy has been described in Amanita phalloides poisoning, but no conclusive evidence supports its use. Antiviral therapy for acute hepatitis B may also potentially have benefit and should be considered in ALF, although studies evaluating this are limited.[94] Entecavir or tenofovir are the preferred agents. No specific therapy is currently recommended for acute hepatitis A. Patients presenting with acute Budd-Chiari syndrome should be considered for prompt initiation of anticoagulation therapy. Hepatic vein angioplasty with stent or transjugular intrahepatic portosystemic shunt placement may be considered in patients not responding to anticoagulation. However, some may ultimately require liver transplantation. A report of the largest series to date of Budd-Chiari ALF cases 24 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Management noted that most were associated with a hypercoagulable state and that early initiation of anticoagulation therapy may be associated with improved survival.[95] In contrast, some causes of ALF are associated with relatively poor outcomes despite administration of specific therapies. Acute Wilson's disease with ALF is associated with high mortality despite measures to decrease serum copper levels, including plasmapheresis, continuous veno-venous haemofiltration, albumin dialysis, or plasma exchange. Chelation therapy for Wilson's disease in the setting of ALF is generally ineffective, may be associated with hypersensitivity, and is not recommended. In acute presentations of autoimmune hepatitis resulting in ALF, corticosteroids may have some benefit, as data suggest that patients treated with corticosteroids may have a higher rate of spontaneous recovery.[5] However, data have also demonstrated no significant survival benefit associated with corticosteroid use and suggest that its use in patients with ALF and high Model for End-Stage Liver Disease (MELD) scores could potentially lead to an increased risk of mortality.[96] In the absence of clear prospective data, the potential benefit of corticosteroids in the setting of ALF is uncertain. Liver transplantation Liver transplantation should be considered in all patients with ALF.[56] Prognostic scoring systems are helpful to identify patients at high risk of mortality, but have limitations and should not be relied upon to select patients for transplantation.[6] Therefore, measures should be taken early during the hospital course to prepare a patient with ALF for transfer to a nearby liver transplant centre. Liver transplantation has a major impact on patient survival in ALF. According to some reports, patients with ALF who undergo liver transplantation have an overall 3-year survival rate of 82%.[8] Patients with ALF who fulfil listing criteria according to the United Network for Organ Sharing (UNOS) may be assigned category Status 1A and listed with top priority for liver allocation. Criteria for UNOS Status 1A designation include: • Age >18 years, life expectancy without a liver transplant of <7 days, onset of encephalopathy within 8 weeks of the first symptoms of liver disease, absence of pre-existing liver disease, admission to an intensive care unit, and 1 of the following: • Ventilator dependence, requirement of renal replacement therapy, or INR >2.0. Patients with acute fulminant Wilson's disease may also be given Status 1A priority. Contraindications to liver transplantation for ALF include severe cardiac or pulmonary disease, AIDS, extrahepatic malignancy, metastatic hepatocellular carcinoma, intrahepatic cholangiocarcinoma, uncontrolled sepsis, irreversible neurological complications (e.g., brain death, intracerebral haemorrhage, intractable sustained raised intracranial pressure), ongoing alcohol or illicit substance abuse, and lack of an adequate social support system.[39] Treatment algorithm overview Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 25 Acute liver failure Management M A N A G E M E N T Acute ( summary ) all patients 1st intensive care management plus liver transplantation assessment plus neurological status monitoring for advanced encephalopathy plus monitoring of blood glucose, electrolytes, and cultures paracetamol-related or with mild to moderate (grade 1 or 2) hepatic encephalopathy plus acetylcysteine with herpes simplex hepatitis plus aciclovir with acute fatty liver of pregnancy or the haemolysis, elevated liver enzymes, and low platelet (HELLP) syndrome plus expedient delivery of the fetus with suspected Amanita phalloides poisoning plus intravenous fluids + gastric lavage + activated charcoal plus benzylpenicillin plus acetylcysteine with autoimmune hepatitis plus methylprednisolone with acute hepatitis B plus oral nucleoside or nucleotide analogue with acute Budd-Chiari syndrome plus anticoagulation adjunct transjugular intrahepatic portosystemic shunt (TIPS) with acute Wilson's disease adjunct measures to decrease serum copper with established UNOS Status 1A priority plus liver transplant 26 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Management Treatment algorithm Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 27 Acute liver failure Management M A N A G E M E N T Acute all patients 1st intensive care management » Intensive care monitoring is mandatory once hepatic encephalopathy is present. The natural history of ALF may be characterised by a rapid deterioration in neurological status, high risk of complications including sepsis and cerebral oedema, haemodynamic instability, and renal failure. Intensive care unit monitoring is critical in providing optimal care of the patient and to prevent and treat known complications of ALF. » Efforts should be made to minimise elevations of intracranial pressure. The head of the patient's bed should be raised to approximately 30 degrees and surrounding stimuli reduced to a minimum.[85] Once advanced encephalopathy develops, tracheal intubation should be performed for airway protection. Propofol and fentanyl are preferred agents for analgesia and sedation due to their short half-lives. Intravenous fluids should be administered with caution to prevent depletion or volume overload; central venous pressure and pulmonary arterial monitoring as well as renal replacement therapy should be considered early to ensure optimal fluid management, particularly if there is evidence of renal or circulatory dysfunction.[59] [6] » Enteral nutrition is generally a concern in the setting of encephalopathy, in which the patient is unable to obtain adequate nutrition due to an altered mental status. Therefore, enteral nutritional support with calorie-dense feeds should also be initiated early during the hospital course. » Prophylactic antimicrobial therapy does not appear to influence outcome.[89] However, empirical antimicrobials are recommended if a patient develops positive surveillance cultures, refractory hypotension, progression to grade 3 to 4 hepatic encephalopathy, evidence of Systemic Inflammatory Response Syndrome; and in all patients who are listed for liver transplantation.[59] » Proton-pump inhibitors or H2 antagonists should be administered as prophylaxis of gastrointestinal bleeding secondary to coagulopathy.[6] plus liver transplantation assessment 28 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Management Acute Treatment recommended for ALL patients in selected patient group » Criteria for United Network for Organ Sharing (UNOS) Status 1A designation include: age >18 years, life expectancy without a liver transplant of <7 days, onset of encephalopathy within 8 weeks of the first symptoms of liver disease, absence of pre-existing liver disease, admission to an intensive care unit, and 1 of the following: ventilator dependence, requirement of renal replacement therapy, or INR >2.0. UNOS status 1A patients are listed with top priority for liver allocation. Wilson's disease may also be given Status 1A priority. » Contraindications to liver transplantation include severe cardiac or pulmonary disease, AIDS, extrahepatic malignancy, metastatic hepatocellular carcinoma, intrahepatic cholangiocarcinoma, uncontrolled sepsis, irreversible neurological complications (e.g., brain death, intracerebral haemorrhage, intractable sustained raised intracranial pressure), ongoing alcohol or illicit substance abuse, and lack of an adequate social support system.[39] plus neurological status monitoring for advanced encephalopathy Treatment recommended for ALL patients in selected patient group » Neurological status should be monitored carefully and regularly for the development of advanced encephalopathy (grade 3 to 4), which is associated with a greater risk of cerebral oedema and intracranial hypertension. » Head of the patient's bed should be raised to 30 degrees and surrounding stimuli reduced. Tracheal intubation and sedation with intravenous propofol or fentanyl should be performed once advanced encephalopathy develops. Central venous pressure monitoring, pulmonary arterial monitoring, and renal replacement therapy should be considered early. plus monitoring of blood glucose, electrolytes, and cultures Treatment recommended for ALL patients in selected patient group » Blood glucose levels should be monitored every 1 to 2 hours by finger stick to assess for hypoglycaemia. Hypoglycaemia should be corrected with intravenous glucose infusion, with a glycaemic target of 140 mg/dl. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 29 Acute liver failure Management M A N A G E M E N T Acute » Serum electrolytes, including sodium, phosphate, potassium, and magnesium, should be monitored at least twice daily and corrected aggressively. » In patients with advanced encephalopathy (grade 3 or 4), surveillance cultures from blood, urine, and sputum should be obtained periodically given the high risk of bacterial and fungal infection; however, no clear impact of prophylactic antimicrobials has been shown. » Other routine laboratory studies such as coagulation activity, blood cell counts, and liver enzymes should also be monitored closely at regular intervals. paracetamol-related or with mild to moderate (grade 1 or 2) hepatic encephalopathy plus acetylcysteine Treatment recommended for ALL patients in selected patient group Primary options » acetylcysteine: 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours; or 150 mg/kg intravenously over 60 minutes as a loading dose, followed by 12.5 mg/kg/hour over 4 hours, then 6.25 mg/kg/ hour » Acetylcysteine therapy should be given in all cases of paracetamol overdose regardless of the dose or timing of paracetamol ingestion. » Oral acetylcysteine may be given in patients with up to grade 1 hepatic encephalopathy. Otherwise intravenous acetylcysteine is preferred. » Acetylcysteine therapy should continue until end points such as improvement of hepatic function by clinical and laboratory parameters have been achieved.[21] [59] with herpes simplex hepatitis plus aciclovir Treatment recommended for ALL patients in selected patient group Primary options » aciclovir: 10 mg/kg intravenously every 8 hours » May have positive impact on clinical outcome.[6] with acute fatty liver of pregnancy or the haemolysis, elevated liver plus expedient delivery of the fetus Treatment recommended for ALL patients in selected patient group 30 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Management Acute enzymes, and low platelet (HELLP) syndrome » May have positive impact on clinical outcome.[6] with suspected Amanita phalloides poisoning plus intravenous fluids + gastric lavage + activated charcoal Treatment recommended for ALL patients in selected patient group Primary options » activated charcoal: 25-100 g as a single dose, repeat every 4-6 hours if required » Continued supportive management includes intravenous fluids. plus benzylpenicillin Treatment recommended for ALL patients in selected patient group Primary options » benzylpenicillin sodium: 2.4 to 4.8 g/day intravenously in 4 divided doses » Amatoxins inhibit hepatocyte RNA polymerase II, leading to cell necrosis. Beta-lactam antibiotics are thought to be hepatoprotective in the setting of amanita toxicity. This has been reported through in vitro experiments, studies with animal models, and in the clinical setting following Amanita phalloides ingestion by humans, in which intravenous penicillin has been associated with clinical recovery and improved survival. The exact mechanism has not been well defined; however, it may be associated with blocking of amatoxin uptake by hepatocytes.[59] [107] [108] plus acetylcysteine Treatment recommended for ALL patients in selected patient group Primary options » acetylcysteine: 140 mg/kg orally as a loading dose, followed by 70 mg/kg every 4 hours; or 150 mg/kg intravenously over 60 minutes as a loading dose, followed by 12.5 mg/kg/hour over 4 hours, then 6.25 mg/kg/ hour » Oral acetylcysteine may be given in patients with up to grade 1 hepatic encephalopathy. Otherwise intravenous acetylcysteine is preferred. » Acetylcysteine therapy should continue until end points such as improvement of hepatic M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 31 Acute liver failure Management M A N A G E M E N T Acute function by clinical and laboratory parameters have been achieved.[21] [59] with autoimmune hepatitis plus methylprednisolone Treatment recommended for ALL patients in selected patient group Primary options » methylprednisolone sodium succinate: 60 mg intravenously once daily » In acute presentations of autoimmune hepatitis resulting in ALF, corticosteroids may have some benefit; however, data are conflicting.[5] [96] In the absence of clear prospective data, this potential benefit is uncertain. with acute hepatitis B plus oral nucleoside or nucleotide analogue Treatment recommended for ALL patients in selected patient group Primary options » entecavir: 0.5 mg orally/nasogastrically once daily OR » tenofovir disoproxil: 300 mg orally/ nasogastrically once daily » Studies are limited, although antiviral therapy may have benefit and should be considered. Entecavir or tenofovir are the preferred agents. with acute Budd-Chiari syndrome plus anticoagulation Treatment recommended for ALL patients in selected patient group » Patients should be assessed for an underlying hypercoagulable disorder or myeloproliferative disease. Anticoagulation therapy (e.g., lowmolecular-weight heparin) should be initiated in all patients. » Budd-Chiari syndrome is defined by hepatic outflow obstruction secondary to thrombosis at the level of the hepatic veins or suprahepatic inferior vena cava in the absence of cardiac disease. A key factor in the pathogenesis of Budd-Chiari syndrome is the presence of an underlying prothrombotic condition, which can be identified in the majority of cases. Thus, all patients presenting with Budd-Chiari syndrome should be considered for immediate anticoagulation therapy. 32 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Management Acute adjunct transjugular intrahepatic portosystemic shunt (TIPS) Treatment recommended for SOME patients in selected patient group » Hepatic vein angioplasty with stent or transjugular intrahepatic portosystemic shunt (TIPS) placement may be considered in patients not responding to anticoagulation. However, some may ultimately require liver transplantation. with acute Wilson's disease adjunct measures to decrease serum copper Treatment recommended for SOME patients in selected patient group » Acute Wilson's disease with ALF is associated with high mortality despite measures to decrease serum copper levels, including plasmapheresis, continuous veno-venous haemofiltration, albumin dialysis, or plasma exchange. Chelation therapy for Wilson's disease in the setting of ALF is generally ineffective, may be associated with hypersensitivity, and is not recommended. with established UNOS Status 1A priority plus liver transplant Treatment recommended for ALL patients in selected patient group » Patients with ALF who fulfil listing criteria, according to the United Network for Organ Sharing (UNOS), may be assigned category Status 1A and listed with top priority for liver allocation. Criteria for UNOS Status 1A designation include: age >18 years, life expectancy without a liver transplant of <7 days, onset of encephalopathy within 8 weeks of the first symptoms of liver disease, absence of pre-existing liver disease, admission to an intensive care unit, and 1 of the following: ventilator dependence, requirement of renal replacement therapy, or INR >2.0. Patients with acute fulminant Wilson's disease may also be given Status 1A priority. » Contraindications to liver transplantation for ALF include severe cardiac or pulmonary disease, AIDS, extrahepatic malignancy, metastatic hepatocellular carcinoma, intrahepatic cholangiocarcinoma, uncontrolled sepsis, irreversible neurological complications (e.g., brain death, intracerebral haemorrhage, intractable sustained raised intracranial pressure), ongoing alcohol or illicit substance abuse, and lack of an adequate social support system.[39] M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 33 Acute liver failure Management M A N A G E M E N T Emerging Non-biological hepatic assist devices Non-biological hepatic assist devices have been developed as a means of temporary liver support in ALF to bridge patients to a point of recovery or liver transplantation. These devices are based on plasma exchange, haemodialysis, haemofiltration, charcoal haemoperfusion, and resin haemoperfusion systems. The most widely studied is the molecular adsorbents recirculating system (MARS). A randomised controlled trial involving MARS failed to demonstrate a survival benefit in patients with ALF; however, a large proportion of patients in this trial underwent liver transplantation within a short interval from enrolment, precluding definitive safety and efficacy assessment.[109] Although improvements in some physiological parameters have been reported in prospective studies, none of these systems has demonstrated a significant impact on clinical end points or overall survival in the setting of ALF.[110] [111] Bioartificial hepatic assist devices Bioartificial or cell-based hepatic assist devices incorporate hepatocytes or other cell types to provide metabolic as well as detoxification function as a means of temporary liver support in ALF. Cell types used in these devices include immortalised cells such as the C3A human hepatoblastoma cell line or primary porcine hepatocytes. Preliminary studies of bioartificial hepatic assist devices have demonstrated safety; however, their utility or efficacy in the setting of ALF has yet to be determined.[112] Liver tissue engineering and hepatocyte transplantation Several small studies have demonstrated the ability to transplant human hepatocytes in the setting of ALF; however, further research will be required to achieve optimal viability, function, and preservation of the transplanted hepatocytes. Efforts towards development of hepatocyte culture systems and tissue engineering may provide a source of hepatocytes or liver tissue in the future that could further advance these methods.[5] Auxiliary transplantation Auxiliary liver transplantation uses a partial liver allograft to provide temporary support and hepatic function in the setting of ALF, allowing the recipient's native liver to recover function. A partial left hepatic lobe or right hepatic lobe is transplanted from the donor to the recipient. This form of transplantation may benefit younger patients; however, it is associated with a greater incidence of postoperative complications and up to 15% of patients ultimately undergo re-transplantation.[113] Primary prevention As paracetamol hepatotoxicity is one of the leading causes of ALF, efforts to prevent unintentional overdose may translate into reductions in cases of ALF. Actions that could prevent ALF include patient, pharmacy, and physician education to avoid prescribing multiple paracetamol-containing preparations and to avoid exceeding maximum daily recommended dosing of paracetamol. Methods to restrict access to paracetamol have been used in Europe with significant reductions of hospital admissions, liver transplants, and deaths associated with paracetamol overdose.[12] Immunisation for hepatitis A and B is currently recommended for all infants in the US.[38] Immunisation strategies for patients with chronic liver diseases to receive hepatitis A and B vaccines may prevent acute superinfection with these viruses and risk of an acute fulminant course. Secondary prevention In hepatitis B surface antigen carriers with surface antigen positivity who undergo treatment with cancer chemotherapy, B-cell depleting agents such as rituximab, long-term corticosteroids, tumour necrosis factoralpha inhibitors, or other forms of immunosuppression, prophylactic antiviral therapy should be initiated at the onset of pharmacotherapy and continued for at least 6 months following completion to prevent acute reactivation of hepatitis B and a potential risk of ALF.[124] [125] Antiviral prophylaxis may also be considered in those with resolved infection, characterised by a positive antibody to hepatitis B core antigen 34 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Management and negative hepatitis B surface antigen, in which the risk of reactivation exists with increasing levels of immunosuppression.[126] Nearly 20% of hepatitis B virus (HBV)-associated ALF cases enrolled in the US Acute Liver Failure Study Group from 1998 to 2015 occurred in the setting of HBV reactivation following immunosuppressive therapy.[127] Patient discussions In patients who recover from ALF and are discharged from the hospital, instructions should be given to follow up with their primary care and speciality care providers on an outpatient basis, for ongoing management and potential treatment of chronic liver disease resulting from ALF. [Patient UK: liver failure] (http://patient.info/doctor/liver-failure) Nutrition is exceedingly important in their recovery from ALF, and patients should be instructed to continue with an adequate diet, including nutritional supplements. All potential hepatotoxic medications as well as non-steroidal anti-inflammatory drugs (NSAIDs) should be avoided during the hospital course and immediately following recovery. Patients who receive a liver transplant will also require close follow-up on an outpatient basis for management of immunosuppressive medication and postoperative care. M A N A G E M E N T This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 35 Acute liver failure Follow up F O L L O W U P Monitoring Monitoring Intensive care unit monitoring during the course of hospitalisation is very important in the management of patients presenting with ALF, in order to provide optimal care and minimise complications. Following spontaneous recovery from ALF, patients should continue follow-up with their primary care and speciality care providers, including hepatologists. Depending on the aetiology of ALF, they may have a subsequent chronic liver disease that requires long-term therapy. Likewise, if a liver transplant is performed, postoperative care including immunosuppression management must be monitored closely. 36 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Follow up Complications Complications Timeframe Likelihood rapidly progressing hepatic encephalopathy long term high Hepatic encephalopathy may progress rapidly in ALF. As the grade of encephalopathy increases, the risk of cerebral oedema increases to as high as 35% and 75%, for grades 3 and 4 encephalopathy respectively.[117] Although commonly used in the management of hepatic encephalopathy and associated hyperammonaemia, lactulose therapy does not appear to have a significant impact on outcomes in ALF. Once encephalopathy progresses to grades 3 or 4, elective tracheal intubation should be performed.[118] Obtaining a computed tomography scan of the head should be considered following tracheal intubation to assess for cerebral oedema or other causes of altered mental status such as intracranial bleeding.[59] coagulopathy long term high Coagulopathy is a defining feature of ALF, yet the incidence of significant acute bleeding is low. Coagulation parameters have prognostic value and may be monitored to assess for on-going hepatic dysfunction or resolution in ALF. Vitamin K may be given for possible vitamin K deficiency; however, correction of coagulopathy is not recommended unless clinically significant bleeding occurs or prior to invasive procedures.[59] In these cases, fresh frozen plasma, platelets, and cryoprecipitate may be given. Recombinant factor VIIa may also be administered, although it is possibly associated with an increased risk of thrombotic events.[123] infection variable high Infection occurs frequently in ALF and remains a primary cause of mortality in this population. Bacterial infections have been reported to occur in over 80% and fungal infections as frequently as 30%.[114] Prophylactic antimicrobial therapy does not appear to influence outcome. However, empirical antimicrobials are recommended if a patient develops positive surveillance cultures, refractory hypotension, progression to grade 3 to 4 hepatic encephalopathy, evidence of Systemic Inflammatory Response Syndrome; and in all patients who are listed for liver transplant.[59] renal failure and haemodynamic changes variable high Renal dysfunction is common in ALF and occurs more frequently in the setting of paracetamol overdose, in which it may appear earlier during the course. The presence of renal failure is highly predictive of mortality in paracetamol overdose, as serum creatinine levels >300 micromol/L (3.4 mg/dL) on presentation may be associated with a mortality rate >75%.[56] Aetiologies of renal failure may include hypovolaemia, acute tubular necrosis, and hepatorenal syndrome. If a patient develops renal or circulatory dysfunction, volume status should be monitored closely, and renal replacement therapy with continuous veno-venous haemodialysis is preferred over intermittent haemodialysis due to improved stability of intracranial pressure and cardiovascular parameters.[115] [116] If vasopressors are required, noradrenaline (norepinephrine) or dopamine are recommended.[59] metabolic disorders variable high Acid-base disturbances may occur, particularly if renal dysfunction is present. Electrolyte and metabolic derangements should be corrected promptly as they may contribute to worsening hepatic encephalopathy and cerebral oedema. Hyponatraemia should be corrected with a target serum sodium concentration of 140-145 mmol/L.[85] Abnormalities in serum phosphate, potassium, and magnesium are common. Hypoglycaemia occurs as a result of impaired gluconeogenesis and decreased hepatic glycogen production. Continuous infusions of glucose at 10% to 20% solutions are preferred over bolus administration.[6] Serum glucose should be corrected to ±7.8 mmol/L (±140 mg/dl).[85] Hyperglycaemia may worsen cerebral oedema and should be avoided. F O L L O W U P This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 37 Acute liver failure Follow up F O L L O W U P Complications Timeframe Likelihood cerebral oedema variable high Cerebral oedema with intracranial hypertension is one of the primary causes of death in ALF and is more commonly associated with a hyperacute presentation. Once cerebral oedema develops, factors that may precipitate elevations of intracranial pressure should be minimised. The head of the patient's bed should be raised to approximately 30 degrees and surrounding stimuli reduced to a minimum.[85] Placement of an intracranial pressure (ICP) monitor may also be considered, particularly in patients who are listed for liver transplant.[119] Non-invasive assessment of intracranial pressure with modalities such as transcranial Doppler may also have a role in estimating cerebral perfusion pressure in patients with cerebral oedema.[120] Specific therapies for elevated ICP include intravenous mannitol bolus, which may be given if the ICP is ≥25 mmHg for >10 minutes. Renal function should be monitored closely or renal replacement therapy initiated as these are essential for mannitol clearance. Repeat boluses may be given if the ICP continues to be ≥25 mmHg and serum osmolality <320 mOsm/L.[59] Boluses of hypertonic saline can also be used to reduce ICP.[85] Hyperventilation to achieve PaCO2 of 25-30 mmHg produces a short-lived reduction in ICP, and may be used to delay uncal herniation in patients with life-threatening intracranial hypertension that is not controlled by other measures. Additional specific therapies for cerebral oedema with intracranial hypertension have been described, including induced moderate hypothermia, induced pentobarbital or thiopental coma, and administration of intravenous indometacin (indomethacin).[59] [118] [121] One large multicentre retrospective study evaluating the role of therapeutic hypothermia in this setting found no difference in overall transplant-free survival; however, young individuals with paracetamol-associated ALF may benefit from this practice.[122] Seizures increase ICP and should be treated with anticonvulsants.[6] gastrointestinal bleeding variable low ALF patients are at risk of gastrointestinal bleeding due to coagulopathy and the requirement for mechanical ventilation.[6] Proton-pump inhibitors or H2 antagonists should be administered as prophylaxis.[6] Prognosis ALF carries a substantial risk of mortality and continues to be a major challenge to clinicians as strategies to improve outcomes are developed. The sudden onset of disease and low incidence of ALF in the general population have limited our ability to study ALF in a prospective manner. However, data from the US Acute Liver Failure Study Group have provided insight into epidemiological trends, outcomes, and the impact of therapies. Epidemiological studies have consistently demonstrated that the most important prognostic indicator in ALF is aetiology. Survival and outcomes ALF secondary to paracetamol overdose, acute hepatitis A, or ischaemic liver injury is associated with a favourable prognosis. Approximately 75% of patients with paracetamol-induced liver injury recover without 38 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Follow up liver transplantation. In contrast, ALF resulting from idiosyncratic drug-induced liver injury, acute hepatitis B, or indeterminate cause has a much lower rate of spontaneous recovery, ranging from 25% to 41%.[11] A fulminant presentation of Wilson's disease carries such a high risk of mortality that establishment of this diagnosis is sufficient to meet listing criteria for emergency liver transplantation.[62] [113] Liver transplant candidacy should be assessed promptly in all patients who present with ALF, as this may be the only form of therapy that will have an impact on survival. A low-factor V level in the presence of hepatic encephalopathy may be predictive of mortality, particularly in patients with ALF secondary to viral hepatitis.[47] Patients with ALF who undergo liver transplantation appear to have a higher risk of death within the first 3 months following transplant, and more commonly require re-transplantation compared with elective cases.[113] However, the 1-year post-transplant survival rate in the US has improved over the last 10 years. Data from the US Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients indicate that patients with ALF who undergo liver transplantation have survival rates of 88% at 1 year and 82% at 3 years.[8] F O L L O W U P This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 39 Acute liver failure Guidelines G UID E LIN E S Diagnostic guidelines Europe Management of acute (fulminant) liver failure (https://www.easl.eu/research/ our-contributions/clinical-practice-guidelines) Published by: European Association for the Study of the Liver Last published: 2017 North America AASLD position paper: the management of acute liver failure (https:// www.aasld.org/publications/practice-guidelines) Published by: American Association for the Study of Liver Diseases Last published: 2011 Acute liver failure: summary of a workshop (http://onlinelibrary.wiley.com/ doi/10.1002/hep.v47:4/issuetoc#group12) Published by: National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Biomedical Imaging and Bioengineering; Office of Rare Diseases of the National Institutes of Health Last published: 2007 Treatment guidelines United Kingdom Extracorporeal albumin dialysis for acute liver failure (https:// www.nice.org.uk/guidance/IPG316) Published by: National Institute for Health and Care Excellence Last published: 2009 Europe Management of acute (fulminant) liver failure (https://www.easl.eu/research/ our-contributions/clinical-practice-guidelines) Published by: European Association for the Study of the Liver Last published: 2017 40 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Guidelines North America AASLD position paper: the management of acute liver failure (https:// www.aasld.org/publications/practice-guidelines) Published by: American Association for the Study of Liver Diseases Last published: 2011 Intensive care of patients with acute liver failure: recommendations of the US Acute Liver Failure Study Group (http://www.ncbi.nlm.nih.gov/ pubmed/17901832) Published by: US Acute Liver Failure Study Group; National Institutes of Health; Food and Drug Administration Last published: 2007 G UID E LIN E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 41 Acute liver failure Online resources O N LIN E R E S O U R C E S Online resources 1. Patient UK: liver failure (http://patient.info/doctor/liver-failure) (external link) 42 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure References Key articles • Lee WM, Squires RH Jr, Nyberg SL, et al. Acute liver failure: summary of a workshop. Hepatology. 2008 Apr;47(4):1401-15. Full text (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381946) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18318440?tool=bestpractice.bmj.com) • American Association for the Study of Liver Diseases. AASLD position paper: the management of acute liver failure: update 2011. November 2011 [internet publication]. Full text (https://www.aasld.org/ sites/default/files/2019-06/AcuteLiverFailureUpdate201journalformat1.pdf) • Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec;42(6):1364-72. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/16317692?tool=bestpractice.bmj.com) • Robinson CL, Bernstein H, Romero JR, et al. Advisory Committee on Immunization Practices recommended immunization schedule for children and adolescents aged 18 years or younger - United States, 2019. MMWR Morb Mortal Wkly Rep. 2019 Feb 8;68(5):112-4. Full text (https://www.cdc.gov/ mmwr/volumes/68/wr/mm6805a4.htm?s_cid=mm6805a4_w) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/30730870?tool=bestpractice.bmj.com) • O'Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97:339-345. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/2490426? tool=bestpractice.bmj.com) • O'Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):339-45. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/2490426? tool=bestpractice.bmj.com) • Roberts EA, Schilsky ML. American Association for Study of Liver Diseases (AASLD). Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008 Jun;47(6):2089-111. Full text (http://onlinelibrary.wiley.com/doi/10.1002/hep.22261/full) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/18506894?tool=bestpractice.bmj.com) • McPhail MJ, Wendon JA, Bernal W. Meta-analysis of performance of Kings's College Hospital Criteria in prediction of outcome in non-paracetamol-induced acute liver failure. J Hepatol. 2010 Sep;53(3):492-9. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20580460?tool=bestpractice.bmj.com) • Wendon J, Cordoba J, Dhawan A, et al; European Association for the Study of the Liver. EASL clinical practical guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017 May;66(5):1047-81. Full text (https://www.journal-of-hepatology.eu/article/S0168-8278(16)30708-5/ fulltext) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28417882?tool=bestpractice.bmj.com) • Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-99. Full text (https:// aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.29800) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/29405329?tool=bestpractice.bmj.com) R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 43 Acute liver failure References R E F E R E N C E S References 1. Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis. 1970;3:282-98. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/4908702?tool=bestpractice.bmj.com) 2. Gimson AE, O'Grady J, Ede RJ, et al. Late onset hepatic failure: clinical, serological and histological features. Hepatology. 1986 Mar-Apr;6(2):288-94. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/3082735?tool=bestpractice.bmj.com) 3. Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis. 1986 May;6(2):97-106. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/3529410? tool=bestpractice.bmj.com) 4. O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993 Jul 31;342(8866):273-5. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/8101303? tool=bestpractice.bmj.com) 5. Lee WM, Squires RH Jr, Nyberg SL, et al. Acute liver failure: summary of a workshop. Hepatology. 2008 Apr;47(4):1401-15. Full text (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381946) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18318440?tool=bestpractice.bmj.com) 6. American Association for the Study of Liver Diseases. AASLD position paper: the management of acute liver failure: update 2011. November 2011 [internet publication]. 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Outcomes in adults with acute liver failure between 1998 and 2013: an observational cohort study. Ann Intern Med. 2016 Jun 7;164(11):724-32. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5526039) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/27043883?tool=bestpractice.bmj.com) 11. Stravitz RT, Lee WM. Acute liver failure. Lancet. 2019 Sep 7;394(10201):869-81. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/31498101?tool=bestpractice.bmj.com) 44 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure References 12. Bernal W, Hyyrylainen A, Gera A, et al. Lessons from look-back in acute liver failure? 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Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/16317692?tool=bestpractice.bmj.com) R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 45 Acute liver failure References R E F E R E N C E S 23. Myers RP, Shaheen AA, Li B, et al. Impact of liver disease, alcohol abuse, and unintentional ingestions on the outcomes of acetaminophen overdose. Clin Gastroenterol Hepatol. 2008 Aug;6(8):918-25. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18486561?tool=bestpractice.bmj.com) 24. Garfein RS, Bower WA, Loney CM, et al. Factors associated with fulminant liver failure during an outbreak among injection drug users with acute hepatitis B. 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Abstract (http://www.ncbi.nlm.nih.gov/pubmed/20723036? tool=bestpractice.bmj.com) 46 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure References 34. Karvellas CJ, Cardoso FS, Gottfried M, et al. HBV-associated acute liver failure after immunosuppression and risk of death. Clin Gastroenterol Hepatol. 2017;15:113-122. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/27311622?tool=bestpractice.bmj.com) 35. Nguyen GC, Sam J, Thuluvath PJ. Hepatitis C is a predictor of acute liver injury among hospitalizations for acetaminophen overdose in the United States: a nationwide analysis. Hepatology. 2008 Oct;48(4):1336-41. 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Full text (https:// www.ncbi.nlm.nih.gov/pmc/articles/PMC4944342) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/27089111?tool=bestpractice.bmj.com) 42. Leventhal TM, Gottfried M, Olson JC, et al. Acetaminophen is undetectable in plasma from more than half of patients believed to have acute liver failure due to overdose. Clin Gastroenterol Hepatol. 2019 Sep;17(10):2110-6. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30731196? tool=bestpractice.bmj.com) 43. Flamm SL, Yang YX, Singh S, et al. American Gastroenterological Association Institute guidelines for the diagnosis and management of acute liver failure. Gastroenterology. 2017 Feb;152(3):644-7. Full text (https://www.gastrojournal.org/article/S0016-5085(16)35540-8/fulltext? referrer=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F28056348%2F%3Ffrom_single_result R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 47 Acute liver failure References R E F E R E N C E S %3D28056348%26expanded_search_query%3D28056348) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/28056348?tool=bestpractice.bmj.com) 44. Rich NE, Sanders C, Hughes RS, et al. Malignant infiltration of the liver presenting as acute liver failure. Clin Gastroenterol Hepatol. 2015 May;13(5):1025-8. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/25277846?tool=bestpractice.bmj.com) 45. Stravitz RT, Lefkowitch JH, Fontana RJ, et al. Autoimmune acute liver failure: proposed clinical and histological criteria. Hepatology. 2011;53:517-526. 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J Clin Gastroenterol. 2016 Jan;50(1):85-91. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/26166142? tool=bestpractice.bmj.com) 50. Chalasani NP, Hayashi PH, Bonkovsky HL, et al; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109(7):950-66. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/24935270?tool=bestpractice.bmj.com) 51. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy: definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology. 2002 Mar;35(3):716-21. Full text (http://onlinelibrary.wiley.com/ doi/10.1053/jhep.2002.31250/pdf) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/11870389? tool=bestpractice.bmj.com) 52. Conn HO, Leevy CM, Vlahcevic ZR, et al. Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology. 1977 Apr;72(4 Pt 1):573-83. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14049? tool=bestpractice.bmj.com) 53. Hawton K, Simkin S, Deeks J, et al. UK legislation on analgesic packs: before and after study of long term effect on poisonings. BMJ. 2004 Nov 6;329(7474):1076. [Erratum in: BMJ. 2004 Nov 13;329(7475):1159.] Full text (http://www.bmj.com/content/329/7474/1076.full) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/15516343?tool=bestpractice.bmj.com) 48 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure References 54. Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014 Jul;147(1):109-18.e5. Full text (http://www.gastrojournal.org/article/S0016-5085(14)00447-8/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/24704526?tool=bestpractice.bmj.com) 55. Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology. 2008 Oct;48(4):1167-74. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18798336?tool=bestpractice.bmj.com) 56. O'Grady JG, Alexander GJ, Hayllar KM, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):339-45. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/2490426? tool=bestpractice.bmj.com) 57. Stravitz RT, Ellerbe C, Durkalski V, et al; Acute Liver Failure Study Group. 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Immune phenotype of chronic liver disease. Dig Dis Sci. 1998 Sep;43(9):2149-55. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/9753285? tool=bestpractice.bmj.com) R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 49 Acute liver failure References R E F E R E N C E S 65. Friedman LS. Liver transplantation for sickle cell hepatopathy. Liver Transpl. 2007 Apr;13(4):483-5. Full text (http://onlinelibrary.wiley.com/doi/10.1002/lt.21031/full) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/17394145?tool=bestpractice.bmj.com) 66. Pauwels A, Mostefa-Kara N, Florent C, et al. Emergency liver transplantation for acute liver failure. 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Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with endstage liver disease. Hepatology. 2001 Feb;33(2):464-70. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/11172350?tool=bestpractice.bmj.com) 74. Wiesner R, Edwards E, Freeman R, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003 Jan;124(1):91-6. Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/12512033?tool=bestpractice.bmj.com) 75. Kremers WK, van IJperen M, Kim WR, et al. MELD score as a predictor of pretransplant and posttransplant survival in OPTN/UNOS status 1 patients. Hepatology. 2004 Mar;39(3):764-9. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/14999695?tool=bestpractice.bmj.com) 50 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure References 76. Zaman MB, Hoti E, Qasim A, et al. MELD score as a prognostic model for listing acute liver failure patients for liver transplantation. Transplant Proc. 2006 Sep;38(7):2097-8. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/16980011?tool=bestpractice.bmj.com) 77. Katoonizadeh A, Decaestecker J, Wilmer A, et al. MELD score to predict outcome in adult patients with non-acetaminophen-induced acute liver failure. Liver Int. 2007 Apr;27(3):329-34. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/17355453?tool=bestpractice.bmj.com) 78. Yantorno SE, Kremers WK, Ruf AE, et al. MELD is superior to King's College and Clichy's criteria to assess prognosis in fulminant hepatic failure. Liver Transpl. 2007 Jun;13(6):822-8. 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EASL clinical practical guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017 May;66(5):1047-81. Full text (https://www.journal-of-hepatology.eu/article/S0168-8278(16)30708-5/ fulltext) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28417882?tool=bestpractice.bmj.com) 86. Soar J, Böttiger BW, Carli P, et al. European Resuscitation Council Guidelines 2021: adult advanced life support. Resuscitation. 2021 Apr;161:115-51. Full text (https://www.doi.org/10.1016/ j.resuscitation.2021.02.010) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/33773825? tool=bestpractice.bmj.com) R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 51 Acute liver failure References R E F E R E N C E S 87. Colquhoun MC, Handley AJ, Evans TR, eds. ABC of resuscitation. 5th ed. Wiley-Blackwell; 2004. 88. Soar J, Böttiger BW, Carli P, et al. European Resuscitation Council Guidelines 2021: adult advanced life support. Resuscitation. 2021 Apr;161:115-51. Full text (https://www.doi.org/10.1016/ j.resuscitation.2021.02.010) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/33773825? tool=bestpractice.bmj.com) 89. Karvellas CJ, Cavazos J, Battenhouse H, et al; US Acute Liver Failure Study Group. Effects of antimicrobial prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin Gastroenterol Hepatol. 2014 Nov;12(11):1942-9.e1. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205208) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/24674942?tool=bestpractice.bmj.com) 90. Stravitz RT. Critical management decisions in patients with acute liver failure. 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Abstract (http://www.ncbi.nlm.nih.gov/pubmed/17382229? tool=bestpractice.bmj.com) 52 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure References 98. McGee DC, Gould MK. Preventing complications of central venous catheterization. N Engl J Med. 2003 Mar 20;348(12):1123-33. Full text (https://www.nejm.org/doi/10.1056/NEJMra011883) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/12646670?tool=bestpractice.bmj.com) 99. Smith RN, Nolan JP. Central venous catheters. BMJ. 2013 Nov 11;347:f6570. Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/24217269?tool=bestpractice.bmj.com) 100. Reich DL. Monitoring in anesthesia and perioperative care. 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Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/12475187?tool=bestpractice.bmj.com) 109. Saliba F, Camus C, Durand F, et al. Albumin dialysis with a noncell artificial liver support device in patients with acute liver failure: a randomized, controlled trial. Ann Intern Med. 2013 Oct 15;159(8):522-31. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/24126646? tool=bestpractice.bmj.com) R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 53 Acute liver failure References R E F E R E N C E S 110. National Institute for Health and Care Excellence. Extracorporeal albumin dialysis for acute liver - interventional procedures guidance. 23 September 2009 [internet publication]. Full text (https:// www.nice.org.uk/guidance/IPG316) 111. MacDonald AJ, Karvellas CJ. Emerging role of extracorporeal support in acute and acute-on-chronic liver failure: recent developments. Semin Respir Crit Care Med. 2018 Oct;39(5):625-34. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30485892?tool=bestpractice.bmj.com) 112. Rela M, Kaliamoorthy I, Reddy MS. Current status of auxiliary partial orthotopic liver transplantation for acute liver failure. Liver Transpl. 2016 Sep;22(9):1265-74. Full text (https:// aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/lt.24509) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/27357489?tool=bestpractice.bmj.com) 113. Liou IW, Larson AM. Role of liver transplantation in acute liver failure. Semin Liver Dis. 2008 May;28(2):201-9. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/18452119?tool=bestpractice.bmj.com) 114. 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Moderate hypothermia with intracranial pressure monitoring as a therapeutic paradigm for the management of acute liver failure: a systematic review. 54 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure References Intensive Care Med. 2010 Feb;36(2):210-3. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/19847396? tool=bestpractice.bmj.com) 122. Karvellas CJ, Todd Stravitz R, Battenhouse H, et al. Therapeutic hypothermia in acute liver failure: a multicenter retrospective cohort analysis. Liver Transpl. 2015 Jan;21(1):4-12. Full text (http://onlinelibrary.wiley.com/doi/10.1002/lt.24021/full) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/25308108?tool=bestpractice.bmj.com) 123. Porte RJ, Caldwell SH. The role of recombinant factor VIIa in liver transplantation. Liver Transpl. 2005 Aug;11(8):872-4. Full text (http://onlinelibrary.wiley.com/doi/10.1002/lt.20447/full) Abstract (http:// www.ncbi.nlm.nih.gov/pubmed/16035071?tool=bestpractice.bmj.com) 124. Lok AS, Ward JW, Perrillo RP, et al. Reactivation of hepatitis B during immunosuppressive therapy: potentially fatal yet preventable. Ann Intern Med. 2012 May 15;156(10):743-5. Full text (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3469313) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/22586011?tool=bestpractice.bmj.com) 125. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-99. Full text (https:// aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.29800) Abstract (http://www.ncbi.nlm.nih.gov/ pubmed/29405329?tool=bestpractice.bmj.com) 126. Reddy KR, Beavers KL, Hammond SP, et al. American Gastroenterological Association Institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015 Jan;148(1):215-9. Full text (http://www.gastrojournal.org/ article/S0016-5085(14)01331-6/fulltext) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/25447850? tool=bestpractice.bmj.com) 127. Karvellas CJ, Cardoso FS, Gottfried M, et al. HBV-associated acute liver failure after immunosuppression and risk of death. Clin Gastroenterol Hepatol. 2017 Jan;15(1):113-22. Abstract (http://www.ncbi.nlm.nih.gov/pubmed/27311622?tool=bestpractice.bmj.com) R E F E R E N C E S This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 55 Acute liver failure Disclaimer DIS C L AIM E R Disclaimer BMJ Best Practice is intended for licensed medical professionals. BMJ Publishing Group Ltd (BMJ) does not advocate or endorse the use of any drug or therapy contained within this publication nor does it diagnose patients. As a medical professional you retain full responsibility for the care and treatment of your patients and you should use your own clinical judgement and expertise when using this product. This content is not intended to cover all possible diagnosis methods, treatments, follow up, drugs and any contraindications or side effects. 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Figure 1 – BMJ Best Practice Numeral Style 56 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. Acute liver failure Disclaimer 5-digit numerals: 10,000 4-digit numerals: 1000 numerals < 1: 0.25 Our full website and application terms and conditions can be found here: Website Terms and Conditions. Contact us + 44 (0) 207 111 1105 support@bmj.com BMJ BMA House Tavistock Square London WC1H 9JR UK DIS C L AIM E R This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 29, 2020. BMJ Best Practice topics are regularly updated and the most recent version of the topics can be found on bestpractice.bmj.com . Use of this content is subject to our disclaimer (. Use of this content is subject to our) . © BMJ Publishing Group Ltd 2021. All rights reserved. 57 Contributors: // Authors: Stevan A. Gonzalez, MD, MS Associate Professor Department of Internal Medicine, TCU and UNTHSC School of Medicine, Medical Director of Liver Transplantation, Annette C. and Harold C. Simmons Transplant Institute, Baylor All Saints Medical Center, Fort Worth, TX DISCLOSURES: SAG declares that he has no competing interests. // Acknowledgements: Dr Stevan Gonzalez would like to gratefully acknowledge the late Dr Emmet B. Keeffe who previously cocontributed to this topic; an esteemed colleague, friend, and mentor. DISCLOSURES: EBK declared that he had no competing interests. // Peer Reviewers: Timothy J. Davern, MD Director of Acute Liver Failure Program California Pacific Medical Center Liver Transplant Program, San Francisco, CA DISCLOSURES: Not disclosed. Muhammad Dawwas, MRCP Specialist Registrar Liver Unit, Addenbrooke's Hospital, Cambridge, UK DISCLOSURES: Not disclosed.