Key words
- Acute liver injury
- Acute liver failure
- Liver transplant centre
- Encephalopathy
- Jaundice
Abbreviations
ACLF – Acute-on-chronic liver failure
ALF – Acute liver failure
ALI – Acute liver injury
CLD – Chronic liver disease
CT – Computed tomography
CVVHF – Continuous veno-venous haemofiltration
DILI – Drug-induced liver injury
GCS – Glasgow coma scale
HE – Hepatic encephalopathy
INR – International normalised ratio
MAP – Mean arterial pressure
LT – Liver transplant
POD – Paracetamol overdose
Learning points
- All cases of acute liver failure should be discussed with a transplant centre for consideration of transfer; however, robust supportive management prior to transfer is crucial.
- For any acute liver injury with significant or worsening (liver-related) coagulopathy, rapid recognition and evaluation of severity should be followed by prompt discussion with a liver transplant centre, facilitating early provision of advice and transfer where appropriate.
- It is important to maintain an awareness of factors which may affect suitability for liver transplantation, such as medical co-morbidities and mental health.
Introduction
Acute liver injury (ALI) is defined as an acute derangement in liver function tests associated with liver-related coagulopathy, in the absence of underlying chronic liver disease (CLD)1. A subset progress to acute liver failure (ALF), a relatively rare syndrome characterised by altered consciousness due to hepatic encephalopathy (HE) in the setting of an ALI. Notably, acute-on-chronic liver failure (ACLF) is a distinct phenomenon, involving rapidly progressive organ failure in the context of established cirrhosis, triggered by superimposed liver injury or extrahepatic precipitants such as infection2.
Worldwide, the leading cause of ALF is viral hepatitis1,3,4. However, in many Western countries such as the UK, Paracetamol overdose (POD) predominates3 (see Table 1). Other aetiologies include non-Paracetamol drug-induced liver injury (DILI), toxic fungi, autoimmune hepatitis (often running a more indolent course but accounting for up to 7% of cases of ALF4), Wilson’s disease, and Budd-Chiari syndrome. In up to 17%, the cause remains undetermined, with such cases labelled as “seronegative hepatitis” (a diagnosis of exclusion).
Table 1. Causes of Acute Liver Failure (as % of cases in the UK)3 | |
Paracetamol overdose | 57 |
Unknown | 17 |
Non-paracetamol drug-induced | 11 |
Other causes* | 7 |
Hepatitis B | 5 |
Hepatitis A | 2 |
Hepatitis E | 1 |
*Other causes include acute Budd-Chiari syndrome, Wilson’s disease, Amatoxin (i.e. toxic mushroom) ingestion, ischaemic hepatitis, and malignant infiltration of the liver3. |
ALF can be subcategorised by time elapsed between onset of jaundice and development of encephalopathy, into “hyperacute” (< 7 days), “acute” (7-28 days), and “subacute” (4-24 weeks) liver failure1,3,5.
Classification of ALF is important, as clinical presentation, management and prognosis vary substantially between categories. Hyperacute presentation confers better prognosis with medical management alone, with subacute cases incurring higher mortality without liver transplant (LT)3,6.
ALF can progress rapidly, so swift recognition and early contact with a LT centre – for all cases of ALF (or ALI with significant or worsening coagulopathy) – are paramount¹. A framework for initial evaluation and management is outlined below, summarising what can be provided locally; however, initial contact should be made pending results of investigations to avoid delays.
Clinical presentation
Aside from jaundice, patients may exhibit non-specific symptoms such as abdominal pain, lethargy and malaise7; with infective aetiologies, fever or gastrointestinal disturbance may be present. In subacute cases, weight loss may ensue. Whilst the hallmark of ALF is encephalopathy, other defining features are coagulopathy, hypoglycaemia, and elevated serum lactate (despite correction of hypovolaemia)1,3. Encephalopathy may initially be subtle, but can evolve rapidly, precipitating loss of intrinsic airway protection1,3,7; thus, cases of ALF should be managed in high-dependency settings.
Assessment and Initial Investigations
The initial work-up should serve to
- Stabilise the patient through robust supportive care
- Determine aetiology
- Acquire baseline investigations and establish severity
- Exclude CLD and causes of secondary liver dysfunction (e.g. ischaemic hepatitis/malignant hepatic infiltration1)
- Ensure timely liaison with an LT centre.
A thorough and focussed history (see Table 2), prior to the development of HE (where feasible), is critical to elucidate aetiology and guide suitability for consideration of LT. Factors preclusive of LT include poor functional status, advanced co-morbidities, dependent substance misuse and severe mental health disorders; all negatively impact an individual’s ability to both survive surgery and engage with post-LT follow-up.
Table 2. History in ALF – specific considerations | |
Presentation | Time from onset of jaundice to encephalopathy Last time patient was clinically well or had normal liver tests (if available) |
Medical background | Co-morbidities (including severe Cardiac and/or Respiratory disease; clotting disorders; systemic inflammatory conditions)1 Previous abdominal surgery Performance status (including independence with activities of daily living) Exercise tolerance |
Drug history | Paracetamol intake Over-the-counter medications (or those acquired online) Herbal remedies (including ingested fungi) Recent antimicrobials |
Social history | Previous self-harm Social support network Alcohol history (including collateral history) Smoking history Travel history Recreational drugs (including intravenous drug use) High-risk sexual behaviour |
Family history | Wilson’s disease Ischaemic heart disease |
Psychiatric history | Current/recent mental state |
Investigations in ALF (see Table 3) centre on ascertaining the severity of liver injury, understanding aetiology, and evaluating the need (and suitability) for medical management versus LT.
Table 3. Baseline investigations in ALF | |
Routine bloods | FBC • U&E • LFT (including split Bilirubin) • Bone profile • Coagulation screen (PT/INR/Fibrinogen) • G&S • CRP • Ammonia |
Arterial blood gases | pH • Lactate • Glucose • Acid-base balance |
Non-invasive liver screen | Viral HAV IgM • HBsAg • anti-Hb core antibody (IgG/IgM) • HCV IgG • HEV RNA • HIV antibody screen • CMV PCR • EBV PCR • HSV PCR • VZV PCR • Parvovirus PCR (+/- others if infective cause suspected, e.g. Leptospira serology) Autoimmune Autoantibody screen (including ANA/AMA/SMA/LKM) • Liver immunoblot • Immunoglobulins Metabolic Paracetamol level • HbA1c • Lipid profile • Iron studies (including Ferritin) • LDH • Caeruloplasmin* (+ 24-hour urinary copper excretion if low) • Copper *Slit lamp examination for Kayser-Fleischer rings if feasible |
Septic screen | Blood cultures (line and peripheral) • CXR • Urine MC&S • Sputum MC&S • Fungal markers (BDG/Galactomannan) |
Imaging | CT Head, Chest, Abdomen and Pelvis (with triple phase liver imaging to assess vasculature) |
Ecg | |
Echocardiogram | Focussing on LV/RV function |
ABG = Arterial blood gas; AMA = Anti-mitochondrial antibody; ANA = Anti-nuclear antibody; BDG = Beta-D-glucan; CMV = Cytomegalovirus; CRP = C-reactive protein; CXR = Chest x-ray; ECG = Electrocardiogram; EBV = Epstein-Barr virus; FBC = Full blood count; G&S = Group and screen; HAV = Hepatitis A virus; Hb = Hepatitis B; HbA1c = Glycated Haemoglobin; HBsAg = Hepatitis B surface antigen; HCV = Hepatitis C virus; HEV = Hepatitis E virus; HIV = Human immunodeficiency virus; HSV = Herpes simplex virus; IgG = Immunoglobulin G; IgM = Immunoglobulin M; INR = International normalised ratio; LDH = Lactate dehydrogenase; LKM = Anti-liver/kidney microsomal antibody; LFT = Liver function tests; MC&S = Microscopy, culture and sensitivity; PT = Prothrombin time; RNA = Ribonucleic acid; SMA = Anti-smooth muscle antibody; U&E = Urea and electrolytes; VZV = Varicella zoster virus. |
Understanding the patient’s clinical and biochemical trajectory is fundamental to determining the need for transfer to a LT centre. In ALF, 6-8 hourly blood tests and gases should be performed to establish trends.
CT imaging of the brain, chest, abdomen, and pelvis (with triple phase liver imaging) should be acquired. This can help to corroborate the diagnosis of ALF (e.g. absence of splenomegaly), exclude vascular aetiology (Budd-Chiari syndrome), and identify contraindications to LT (such as active malignancy or severe acute pancreatitis8). Notably, subacute cases may exhibit features of portal hypertension, mimicking decompensated cirrhosis. In the presence of altered consciousness, brain imaging is necessary to exclude structural pathology and assess for radiological evidence of cerebral oedema.
Liver biopsy (via the transjugular route) is rarely indicated in ALF, but may be considered in more indolent sub-acute cases in the absence of an identified drug or viral precipitant7.
Management
The principles of ALF management in the non-transplant centre (including system-specific considerations) are briefly outlined below. Patients with ALF can deteriorate rapidly from multi-organ failure, and should be cared for in a high-dependency or intensive care unit.
Cardiovascular/Respiratory: ALF patients are usually intravascularly deplete, so hypotension mandates aggressive initial fluid resuscitation; where response is inadequate, inotropes (including Noradrenaline and Vasopressin) are utilised to maintain adequate mean arterial pressure (MAP)1.
Neurological: Endotracheal intubation to ensure airway protection is indicated in Grade 3-4 HE1,3,9. Patients risk raised intracranial pressure from cerebral oedema driven by hyperammonaemia11. Neuroprotection is mandated (including nursing at 30º, Sodium control targeting 145-150mmol/L, high-volume CVVHF to lower ammonia levels, and avoidance of hypercapnia), and can be guided by LT centre intensivists.
Microbiological: ALF patients are vulnerable to bacterial and fungal infections, which can preclude LT or increase post-LT mortality11. Prophylactic broad spectrum antibiotics and anti-fungals are indicated.
Haematological: Prothrombin time/INR is a key marker of hepatic function, informing prognosis and guiding the need for LT3. Parenteral Vitamin K (10mg) should be administered, but coagulopathy should not be corrected without clear rationale (i.e. if bleeding)1,3, or following discussion with the LT centre.
Hepatological: N-acetylcysteine is indicated for all ALF patients, irrespective of aetiology1,3,12.
Gastrointestinal: Enteral feeding should be commenced, with laxatives and enemas employed to facilitate regular bowel motions.
Renal: Acute kidney injury is common13, with early CVVHF recommended.
Metabolic: Patients are at risk of hypoglycaemia, and blood glucose should be checked hourly. Phosphate may fall rapidly, requiring aggressive replacement.
Prognostic models (such as the King’s College criteria14) identify those unlikely to survive with medical management alone, thus guiding consideration of LT; both EASL1 and the UK Liver Transplantation guidelines15 also offer recommendations on thresholds for tertiary centre referral (see Table 4). Centres should not, however, wait until patients fulfil such criteria before initiating contact; a diagnosis of ALF should prompt immediate liaison with a LT centre.
Table 4. Suggested criteria for referral to a liver transplant centre1,15 | |
Paracetamol-related | Non-Paracetamol aetiologies |
Arterial pH <7.30 or HCO3 <18mmol/L | Arterial pH <7.30 or HCO3 <18mmol/L |
INR>3.0 (Day 2) or >4.0 (thereafter) | INR >1.8 |
Oliguria or AKI | Oliguria or AKI or Na <130mmol/L |
Encephalopathy | Encephalopathy or Hypoglycaemia or Metabolic acidosis |
Hypoglycaemia | Bilirubin >300µmol/L |
Elevated arterial Lactate* (despite fluid resuscitation) | Shrinking liver size† |
The above table reflects referral thresholds suggested by both EASL1 and the UK Liver Transplant Guidelines15 with the following caveats: †EASL1 additionally include falling liver volumes (which can be estimated radiologically from serial cross-sectional imaging); *the UK Liver Transplantation Guidelines15 define elevated Lactate as >4mmol/L (whereas this is not quantified in the EASL recommendations). Note that a Lactate >3mmol/L despite adequate fluid resuscitation has been demonstrated to be a marker of poor prognosis in Paracetamol-related ALF16. AKI = Acute kidney injury; HCO3 = Bicarbonate; INR = International normalised ratio; Na = Sodium. |
Summary
ALI can evolve rapidly into ALF, therefore prompt recognition and early effective treatment are paramount. Optimal delivery of care for such patients mandates a comprehensive diagnostic work-up, prompt acquisition of key investigations, and efficient liaison with a transplant centre.
Author Biographies
Dr Alexander Hung
Alexander Hung is a Specialty Registrar and Clinical Research Fellow in Hepatology at the Royal Free Hospital. He graduated from University College London in 2014, and is currently working towards a PhD in Hepatology.
Dr Rachel Westbrook
Rachel Westbrook is a Consultant Hepatologist at the Royal Free Hospital, with subspecialty interest in Transplant Hepatology.
CME
SSG Digest This! Acute Decomposition of Liver Disease
10 July 2024
Managing alcohol-related hepatitis and alcohol-related cirrhosis
27 February 2024
How I investigate abnormal liver function test in a patient with IBD
09 January 2024
- European Association for the Study of the Liver. EASL clinical practice guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66:1047-1081.
- Jalan R, Gines P, Olson JC et al. Acute-on-chronic liver failure. J Hepatol. 2012;57(6):1336-1348.
- Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369:2525-2534.
- Stravitz RT, Lee WM. Acute liver failure. Lancet 2019;394(10201):869-881.
- Tandon BN, Bernuau J, O’Grady J et al. Recommendations of the International Association for the Study of the Liver Subcommittee on nomenclature of acute and subacute liver failure. J Gastroenterol Hepatol 1999;14:403–404.
- Blackmore L, Bernal W. Acute liver failure. Clinical Medicine 2015;15(5):468-472.
- Gonzalez SA. Acute liver failure. BMJ Best Practice. May 2020. https://bestpractice.bmj.com/topics/en-gb/1010. Last cited March 2022.
- O’Grady J. Timing and benefit of liver transplantation in acute liver failure. J Hepatol. 2014;60:663–670.
- Polson J, Lee WM. American Association for the Study of Liver Disease. AASLD position paper: the management of acute liver failure. Hepatology 2005;41:1179-1197.
- Bernal W, Hall C, Karvellas CJ et al. Arterial ammonia and risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 2007;46(6):1844-1852.
- Rolando N, Philpott-Howard J, Williams R. Bacterial and fungal infection in acute liver failure. Semin Liver Dis. 1996;16(4):389-402.
- Walayat S, Shoaib H, Asghar M et al. Role of N-acetylcysteine in non-acetaminophen-related acute liver failure: an updated meta-analysis and systematic review. Ann Gastroenterol. 2021;34(2):235-240.
- Betrosian AP, Agarwal B, Douzinas EE. Acute renal dysfunction in liver diseases. World J Gastroenterol. 2007;13(42):5552-5559.
- O’Grady JG, Alexander GJ, Hayllar KM et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989;97(2):439-445.
- Millson C, Considine A, Cramp ME et al. Adult liver transplantation: A UK clinical guideline – part 1: pre-operation. Frontline Gastroenterology 2020;11:375-384.
- Bernal W, Donaldson N, Wyncoll D et al. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002 Feb 16;359(9306):558-563.