Hepatology Snapshot:

JOURNAL
Acute liver failure OF HEPATOLOGY
William Bernal1*, Mark J. McPhail1
1Liver
Intensive Therapy Unit, Institute of Liver Studies, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom
*Corresponding author: Liver Intensive Therapy Unit, Institute of Liver Studies Kings College Hospital, Denmark Hill, London SE5 9RS, United Kingdom; Tel.: +44 203 299 4458.
E-mail address: william.bernal@kcl.ac.uk (W. Bernal).

A rare, complex critical illness Clinical care focuses on4

1. Early recognition and limitation of hepatic injury by addressing its cause and cofactors.
Massive liver cell death in a previously normal liver may result from apoptotic, necrotic or necroptotic mechanisms,
2. Intensive care measures to address MOF, limit complications and optimise hepatic regeneration.
depending on the cause of liver injury.1 The clinical phenotype of acute liver failure (ALF) reflects the nature and extent
3. Continuous assessment of hepatic function and likelihood of native liver recovery.
of liver damage, its rate of evolution and adequacy of hepatic regeneration.
4. Emergency liver transplantation when liver recovery is not expected.
Globally, cases with rapid onset from viral or drug-induced injury are most common with complex immune dysregulation
and multiorgan failure (MOF).2 The illness is changing and survival is improving
1. Hepatocyte death triggers release of Damage-associated molecular patterns (DAMPs) that activate immune cells in Though ALF remains a critical illness with significant mortality, in recent years patient survival has markedly improved.5,6
the liver and circulation.
2. Loss of hepatic function with hyper-ammonaemia and “spill over” of intra-hepatic inflammatory mediators cause
systemic effects with hepatic encephalopathy (HE) and extra-hepatic organ dysfunction.
3. Immune compromise follows, with complicating sepsis a major cause of later morbidity and mortality. Cerebral Oedema
is becoming rarer
Cases with gradual onset are rarer, often of indeterminate cause, and have much less prominent systemic features until
a very late stage of illness. However, liver regeneration is often inadequate and liver transplantation life saving.3
Intracranial hypertension (ICH) from
cerebral œdema complicating HE
Immune dysregulation was a leading cause of death. Better
in the pathogenesis of ALF Monocytes CD64 Neutrophils understanding of pathophysiology
CD163 CD62L has made targeted neuroprotection
CCR7 IL8
Liver transplantation possible.
Monocytes CD64 Neutrophils IL6 CD16 is less often required Prevention of sepsis, early control of
CD163 TNF circulating ammonia, with normother-
CD62L Phagocytosis
CCR7 HLA-DR mia, hemodynamic and metabolic
IL8 Medical support alone is increasingly
IL6 stability have been followed by a fall
TLR9 successful in supporting many patients to
TNF Later immune compromise in the prevalence of ICH.5,7
effective liver regeneration and recovery,
ROS
particularly when liver injury has rapid
evolution.5,6
Monocyte activation
Neutrophil activation Hepatic and
DAMPs/mediators systemic Infection
inflammation
Macrophage activation
CD64 Bleeding complications
CD163 are now uncommon
DNA CCR7 Established treatments
DAMPs Histone IL6 Functional tests of coagulation suggest that are now used in different ways
HMGB1 TNF balanced loss of pro- and anti-coagulant
Chemokines factors result in a normal or even prothrom- Continuous veno-venous haemofiltration
Gluconeogenesis botic state.8 (CVVHF) lowers circulating ammonia
Ureagenesis Bleeding now occurs in <10% of patients and concentration and may be used at high
Hepatocyte death Complement coagulation support is seldom required.9 filtration rates. Its use is associated with
Acute phase proteins improved survival.10,11
Therapeutic plasma exchange has complex
Loss of Coagulation proteins
immunological effects in ALF and in a
hepatic function Ammonia randomised controlled trial improved
Inadequate hepatic Lactate survival.12
regeneration How best to target this intervention is
currently being explored.

Hepatic and extra-hepatic organ failure

Liver Brain Circulation Kidney Lungs Pancreas Adrenal

Keywords: Acute Liver Failure, Critical Care, Liver Transplantation, Encephalopathy

Received 16 December 2020; received in revised form 18 January 2021; accepted 19 January 2021. Journal of Hepatology 2020 vol. x | xxxx-xxxx
Hepatology Snapshot

Financial support [4] European Association for the Study of the Liver. EASL clinical practical
The authors received no financial support to produce this guidelines on the management of acute (fulminant) liver failure. J Hepatol
2017;66:1047–1081.
manuscript. [5] Bernal W, Hyyrylainen A, Gera A, Audimoolam VK, McPhail MJ, Auzinger G,
et al. Lessons from look-back in acute liver failure? A single centre expe-
Conflict of interest rience of 3300 patients. J Hepatol 2013;59:74–80.
The authors declare no conflicts of interest that pertain to this [6] Reuben A, Tillman H, Fontana R, Davern T, McGuire B, Stravitz R, et al.
Outcomes in adults with acute liver failure between 1998 and 2013: an
work.
observational cohort study. Ann Intern Med 2016;164:724–732.
Please refer to the accompanying ICMJE disclosure forms for [7] MacDonald AJ, Speiser JL, Ganger DR, Nilles KM, Orandi BJ, Larson AM, et al.
further details. Clinical and neurologic outcomes in acetaminophen-induced acute liver
failure: a 21-year multicenter cohort study. Clin Gastroenterol Hepatol
Authors’ contributions 2020 Sep 10;S1542-3565(20)31273-8.
[8] Lisman T, Bakhtiari K, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT. Intact
Both authors contributed to the content, design and execution of thrombin generation and decreased fibrinolytic capacity in patients with
the figure. acute liver injury or acute liver failure. J Thromb Haemost 2012;10:1312–
1319.
Supplementary data [9] Stravitz RT, Ellerbe C, Durkalski V, Schilsky M, Fontana RJ, Peterseim C, et al.
Bleeding complications in acute liver failure. Hepatology 2018;67:1931–
Supplementary data to this article can be found online at https://
1942.
doi.org/10.1016/j.jhep.2021.01.037. [10] Warrillow S, Fisher C, Bellomo R. Correction and control of hyper-
ammonemia in acute liver failure: the impact of continuous renal
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