Key words

1. Acute liver injury
2. Acute liver failure
3. Liver transplant centre
4. Encephalopathy
5. 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

1. 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.
2. 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.
3. 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 hepatitis^1,3,4. 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).

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 failure^1,3,5.

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 protection^1,3,7; thus, cases of ALF should be managed in high-dependency settings.

Assessment and Initial Investigations

The initial work-up should serve to

1. Stabilise the patient through robust supportive care
2. Determine aetiology
3. Acquire baseline investigations and establish severity
4. Exclude CLD and causes of secondary liver dysfunction (e.g. ischaemic hepatitis/malignant hepatic infiltration¹)
5. 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.

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.

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 HE^1,3,9. 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 aetiology^1,3,12.

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.

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