Clinical Practice. Guidelines Acute liver failure

clinical practice guidelines on the management of acute (fulminant) liver failure
The guidelines were published in full in the May 2017 issue of the Journal of Hepatology
The full publication can be downloaded from the Clinical Practice Guidelines section of the EASL website
Please cite the published article as: European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of acute (fulminant) liver failure. J Hepatol 2017;66:1047–81
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These slides are intended for use as an educational resource and should not be used in isolation to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials

Frederik Nevens, Didier Samuel, Kenneth J Simpson, Ilan Yaron, Mauro Bernardi (EASL Governing Board Representative)
Reviewers
Ali Canbay, François Durand, Ludwig Kramer

Guideline panel

EASL CPG ALF. J Hepatol 2017;66:1047–81

Guyatt GH, et al. BMJ. 2008:336:924–6; EASL CPG ALF. J Hepatol 2017;66:1047–81

chronic autoimmune hepatitis, Wilson disease and Budd–Chiari syndrome are considered as having ALF if they develop hepatic encephalopathy, despite the presence of a pre-existing liver disease in the context of appropriate abnormalities in liver blood tests and coagulation profile; †Usually INR >1.5 or prolongation of PT
EASL CPG ALF. J Hepatol 2017;66:1047–81

In hepatological practice, ALF is a highly specific and rare syndrome, characterized by an acute deterioration of liver function without underlying chronic liver disease

W, et al. Lancet 2010;376:190−201;
EASL CPG ALF. J Hepatol 2017;66:1047–81

Weeks from development of jaundice to development of HE1

+++ High severity; ++ Medium severity; + Low severity; +/- Present or absent

whose true prevalence across Europe is unknown
Incidence of virally induced ALF has declined substantially in Europe
Remains the most common cause worldwide
Most frequent aetiology of ALF in Europe is now drug-induced liver injury (DILI)

that are not: HAV, HBV, HEV, paracetamol or other drugs
Bernal W, Wendon J. New Eng J Med 2013;369:2525−34

Top three causes of ALF in selected countries

kidney injury and renal replacement therapy
Coagulation
Sepsis, inflammation and anti-inflammatory
The brain in ALF
Artificial and bioartificial liver devices
Liver transplantation
Paediatric ALF

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cirrhosis, alcohol-induced liver injury or malignant infiltration
Initiate early discussions with tertiary liver/transplant centre
Even if not immediately relevant
Screen intensively for hepatic encephalopathy
Determine aetiology
To guide treatment and determine prognosis
Assess suitability for liver transplant
Contraindications should not preclude transfer to tertiary liver/transplant centre
Transfer to a specialized unit early
If the patient has an INR >1.5 and onset of hepatic encephalopathy or other poor prognostic features

route, in an experienced centre, with access to a histopathologist with liver experience
EASL CPG ALF. J Hepatol 2017;66:1047–81

Immediate measures
Exclude cirrhosis, alcohol-induced liver injury or malignant infiltration
Initiate early discussions with tertiary liver/transplant centre
Even if not immediately relevant

aetiology to guide treatment, especially LTx

Primary or secondary causes of ALF and need for transplantation

No indication for emergency LTx

Possible indication for emergency LTx

indication for emergency LTx

Possible indication for emergency LTx

infiltration of the liver and acute ischaemic injury are not indications for LTx

liver injury is the most frequent cause of severe ALI and ALF
Especially paracetamol overdose

and autoimmune ALF
HBV (most common), HAV, HEV, and VZV, HSV-1 and -2 (rare) can cause ALF
Existence of other autoimmune conditions should raise suspicion of autoimmune hepatitis

aetiologies
In most cases a potential positive effect of specific intervention will be too late to be beneficial
Consideration for emergency LTx should not be delayed

required
EASL CPG ALF. J Hepatol 2017;66:1047–81

Questions for patients and relatives at admission

kinase;
†Low urea is a marker of severe liver dysfunction;
‡ANAs, ASMA, anti-soluble liver antigen, globulin profile, ANCAs, HLA typing
EASL CPG ALF. J Hepatol 2017;66:1047–81

CPG ALF. J Hepatol 2017;66:1047–81

In case of HE
Transfer to an appropriate level of care (ideally critical care) at the first symptoms of mental alterations
Quiet surrounding, head of bed >30°C, head in neutral position and intubate, ventilate, and sedate if progression to >3 coma
Low threshold for empirical start of antibiotics if haemodynamic deterioration and/or increasing encephalopathy with inflammatory phenotype
In case of evolving HE, intubation and sedation prior to the transfer
Ensure volume replete and normalize biochemical variables (Na, Mg, PO4, K)

suitability for liver transplant and initiate early discussions with transplant unit
Even if not immediately relevant

Suggested criteria for referral of cases of ALF to specialist units

to a specialized unit early
Evolution of ALF is highly unpredictable
Experience of specialized units is required to improve patient outcomes

haemostasis
Thrombocytopenia

Infection

Bacterial, fungal
Pneumopathy
Septicaemia
Urinary infection

Haemodynamic

Hyperkinetic syndrome
Arrhythmia

Neurological = cerebral oedema

Acute liver failure

Pulmonary

Pneumopathy
Acute respiratory distress syndrome
Pulmonary overload

Cranial hypertension

Brain death

Metabolic

Hypoglycaemia
Hyponatraemia
Hypophosphotaemia
Hypokalaemia

Renal

Toxic
Functional

ALF or severe ALI develop systemic vasodilation with reduced effective central blood volume

required in the face of progression to high-grade HE to ensure airway protection

in patients with ALF is largely empirical
Oral nutrition should be encouraged in patients with ALI
Progressive HE or anorexia is likely to result in decreased calorie intake

with electrolyte and metabolic imbalance
Hypoglycaemia and hyponatraemia
Acidosis
Alterations in serum phosphate, magnesium, ionised calcium and potassium

ALF patients referred to liver units have AKI
Associated with increased mortality and longer hospital stays
Increased age, paracetamol-induced ALI, SIRS, hypotension, and infection increase risk

value
Common in ALF
Thrombocytopenia
Reduced circulating pro- and anti-coagulant proteins
Increased PAI-1
Abnormal coagulation does not translate to increased risk of bleeding
Most patients’ coagulation is normal despite abnormal INR and PT

Coagulation: monitoring and management

1. Agarwal B, et al. J Hepatol 2012;57:780–6; EASL CPG ALF. J Hepatol 2017;66:1047–81

coagulation or platelet levels is not necessary
May instead adversely affect prognosis
May increase the risk of thrombosis or transfusion-related acute lung injury

ALF. J Hepatol 2017;66:1047–81

Patients with ALF are at increased risk of developing infections, sepsis and septic shock
Severe, untreated infection may preclude LTx and complicate the post-operative course
ALF is associated with dynamic immune dysfunction
Imbalance can contribute to organ failure and death

tends to fluctuate
May progress from a trivial lack of awareness to deep coma
Multiple additional manifestations
Headache, vomiting, asterixis, agitation, hyperreflexia and clonus
Clinical diagnosis is one of exclusion
Course dictated by outcome and phenotype of liver failure
Usually parallels evolution of liver function parameters
Neurological outcomes may be worse in some circumstances
Coexistence of infection
Presence of inflammation without sepsis
Other organ failure

context is not defined by asterixis (hepatic flap) but by the development of marked agitation and frequent aggression with a decrease in GCS (usually E1–2, V 3–4 and M4); †Grade 4 coma is associated with marked reduction in GCS (E1, V 1–2 and M1–3); ‡This may protect from ICH and reduce the risk of seizures; §E.g. levetiracetam or lacosamide (prophylactic use of antiepileptic drugs is not warranted)
EASL CPG ALF. J Hepatol 2017;66:1047–81

Regular clinical and neurological examination to monitor progression in a quiet environment
On progression to Grade 3 HE:*
Intubate and provide mechanical ventilation to protect the airway, prevent aspiration and provide safer respiratory care
On progression to Grade 4 HE:†
Minimize risk of pulmonary barotraumas
Target PaCO2 between 4.5–5.5 kPa (34–42 mmHg) and use propofol as a sedative agent‡
Add a short-acting opiate for adequate analgesia
In case of concern of seizure activity:
Monitor EEG
Administer antiepileptic drugs with low risk of hepatotoxicity§

of ICH has decreased recently1
Improvements in preventative medical care
Use of emergency LTx in high-risk patients2
Still may affect one-third of cases who progress to Grade 3 or 4 HE
Risk of ICH is highest in patients with:
Hyperacute or acute phenotype
Younger age
Renal impairment
Need for inotropic support
Persistent elevation of arterial ammonia

The brain in ALF: intracranial hypertension

*Proportion of 1,549 patients with ALF developing clinical signs of ICH. Error bars are 95% CI; p<0.00001 1. Bernal W, et al. J Hepatol 2013;59:74–80; 2. Bernal W, et al. J Hepatol 2015;62(1 Suppl):S112–20;
EASL CPG ALF. J Hepatol 2017;66:1047–81

neurological examination is mandatory
Detection of early signs of HE and progression to high-grade HE is critical

required in some patients

15% of ideal body weight with fresh frozen plasma, for 3 days was superior to SMT regarding transplant-free and overall hospital survival
Larsen FS, et al. J Hepatol. 2016;64:69–78; EASL CPG ALF. J Hepatol 2017;66:1047–81

Liver-assist devices are intended to provide a ‘bridge’ to LTx or recovery of liver function, reducing the need for transplant
Experience with “liver support devices” to date has been disappointing
High-volume plasma exchange improved outcome in an RCT in ALF*

2012;57:288–96;
EASL CPG ALF. J Hepatol 2017;66:1047–81.

LTx has been the most significant development in the treatment of ALF in 40 years and has transformed survival
1-year survival following emergency LTx for ALF is now around 80%
Selection for LTx depends on:
Accurate prediction of survival without transplant
Consideration of the survival potential after LTx
Consideration of whether a patient is too sick to transplant

Patient survival after liver transplantation for ALF, Europe 1988–20091

p<0.001 for survival 2004–2009 vs. previous time periods

for transplantation
Common prognostic criteria:
Patient age
Presence of HE
Liver injury severity (magnitude of coagulopathy or jaundice)
In general, falling aminotransferases, increasing bilirubin and INR, and shrinking liver are poor prognostic signs
Should result in considering transfer of patient to a transplant centre

ALF poor prognosis criteria in use for selection of candidates for liver transplantation

*Bilirubin not included in paracetamol criteria EASL CPG ALF. J Hepatol 2017;66:1047–81

alternatives

*Gc-globulin is a multifunctional protein involved in the scavenging of actin released from necrotic cells1
1. Schiodt FV et al. Liver Transpl 2005;11:1223–7;
EASL CPG ALF. J Hepatol 2017;66:1047–81

Many new marker studies report better diagnostic performance than existing criteria
Often small in size, have limited methodological quality and are seldom internally or externally validated
Few (if any) have been adopted internationally and cannot be recommended for routine use

key at the earliest opportunity

key at the earliest opportunity

Suppl 2:S80-4.

331 patients with acute liver failure, data from the USA and Canada (PALFSG data set)

is the only proven treatment that has improved outcomes in children with ALF who fulfil poor prognostic criteria

ALI to ALF
Improved tests for subtle HE
Review of INR/PT cut-off for definition of ALF in the context of hyperacute, acute and subacute liver failure

Burden of ALF within Europe
Enrolment of all patients with ALF into a common web-based database with internationally agreed definitions of ALF and sub-classification
Internationally accepted assessment of coagulation abnormalities in ALF
Development of EU-wide epidemiological studies to define ALF and ALI prevalence and incidence

General support management outside ICU
Biomarkers to help predict deterioration and likely progression of disease
Assessment of volume status and appropriate fluids in a ward setting.
Point of care assessment for sepsis

Assessment and management at presentation
Further continuous update of the EALFR
Review of criteria defining poor prognosis in the context of modern critical care and support
Application of biomarkers to further delineate cofactors in the development of ALF (e.g. paracetamol adducts, viral nucleic acid testing)

Burden, definition, assessment, and management

EASL CPG ALF. J Hepatol 2017;66:1047–81

Considerations for future studies

assessment of ICP should be developed and validated
Relationship between inflammation and cerebral irritation
Modulators of cerebral inflammation need to be studied

Cardiovascular
Accurate assessment of volume status with biomarkers for congestion and depletion
Studies of microcirculatory status as an endpoint for resuscitation as opposed to pressures
Appropriate utilization of VA ECMO in subgroups of patients with ALF and hypoxic hepatitis

Renal
Monitoring and management of anticoagulation of extracorporeal circuits
Appropriate indications for commencing RRT
Biomarkers for the prediction of and recovery from AKI

Coagulation
Role of anticoagulation to improve microcirculation and decrease liver injury
Further understanding of coagulation disturbances and critically ill patients with ALF, as well as point of care monitoring
Risk of thrombotic complications in the context of ALF and appropriate therapeutic interventions

Sepsis, inflammation and anti-inflammatory
Integration of inflammatory biomarkers with biochemical and functional markers of liver function
Biomarkers to separate infection and inflammation
Immunomodulatory therapy to promote liver regeneration and decrease nosocomial sepsis

Considerations for future studies