Acute liver failure: an up-to-date approach

Filipe S. Cardoso MD MSc, Paulo Marcelino, Luı́s Bagulho, Constan-

tine J. Karvellas

PII: S0883-9441(16)30403-8
DOI: doi: 10.1016/[Link].2017.01.003
Reference: YJCRC 52383

To appear in: Journal of Critical Care

Please cite this article as: Cardoso Filipe S., Marcelino Paulo, Bagulho Luı́s, Karvel-
las Constantine J., Acute liver failure: an up-to-date approach, Journal of Critical Care
(2017), doi: 10.1016/[Link].2017.01.003

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 ACCEPTED MANUSCRIPT

Acute liver failure: an up-to-date approach

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1 1 1 2
Filipe S. Cardoso , Paulo Marcelino , Luís Bagulho , Constantine J. Karvellas

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Intensive Care Unit, Curry Cabral Hospital, Central Lisbon Hospital Center, Lisbon, Portugal
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Divisions of Gastroenterology (Liver Unit) and Critical Care, University of Alberta Hospital, Edmonton,

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Canada

Corresponding author:

Filipe S. Cardoso, MD MSc NU

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Polyvalent Intensive Care Unit, Curry Cabral Hospital, Central Lisbon Hospital Center

Rua da Beneficência, n.º 8, 1069-166 Lisbon, Portugal

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Telephone: +351 21 792 4200

Fax: + 351 21 792 4392

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E-mail: filipe_sousacardoso@[Link]
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Conflicts of interest: none.

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Funding: none.

Abstract word count: 76

Manuscript word count (without abstract and references): 3276

Tables: 6
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ABSTRACT

Acute liver failure is a rare but potentially devastating disease. Throughout the last few decades, ALF

outcomes have been improving in the context of the optimized overall management. This positive trend has

been associated with the earlier recognition of this condition, the improvement of the intensive care unit

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management, and the developments in emergent LT. Accordingly, we aimed to review the current diagnostic

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and therapeutic approach to this syndrome, especially in the intensive care unit setting.

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Keywords: hepatitis; liver failure; critical care.

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INTRODUCTION

Acute liver failure (ALF) is a rare condition characterized by new and rapidly evolving hepatic dysfunction

associated with neurological dysfunction and coagulopathy. It is more frequent in young individuals and its

etiologies vary geographically, with impact on both clinical course and outcomes. Throughout the last

decades, ALF outcomes have been improving in the context of the optimized overall management. However,

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its present morbidity and mortality remain high in patients fulfilling poor prognostic criteria and without

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emergent liver transplantation.

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DEFINITION AND EPIDEMIOLOGY

ALF definition has evolved throughout the time and presently includes the following features: INR ≥1.5,

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neurological dysfunction with any degree of hepatic encephalopathy (HE), no preexisting cirrhosis, and

disease course ≤26 weeks [1]. Exceptions to this definition may be patients with acute presentations of
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Wilson's disease, auto-immune hepatitis, or vertically-transmitted hepatitis B if by the time of the new hepatic

insult they also have underlying cirrhosis known for ≤26 weeks.
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ALF has been subdivided in 3 phenotypes based on the time between jaundice and HE onset (Table 1):

hyperacute (within 7 days), acute (8 to 28 days), or subacute (5 to 26 weeks) [2]. However, the clinical utility
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of this classification has not been entirely clarified as its impact on outcomes seems to be mostly associated

with underlying etiologies [3].

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ALF incidence has been reported as fewer than 10 cases per million people per year in developed countries

[4]. Its etiologies vary worldwide: while in eastern developing countries, viruses (mainly hepatitis A, B or E)
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may account for up to 95% of all ALF cases, the western developed countries have reported more

heterogeneous causes of ALF [5]. In the United Kingdom and the United States of America, acetaminophen

overdose has been the leading cause of ALF [3,6]. In other parts of Europe (e.g. Germany and Portugal), the

most common causes of ALF have been non-acetaminophen drug-induced liver injury, seronegative

(indeterminate) liver injury, and viruses (mostly hepatitis B) [7,8]. ALF etiologies are summarized in Table 2

[1,3,4,9].

ALF outcomes have been improving throughout the decades with overall hospital survival increasing from

17% in 1973-1978 to 62% in 2004-2008 in a single center from the United Kingdom [10]. In a multicenter

registry from the United States of America in 1998-2010, ALF 2-year survival has been reported as 92% for

liver transplant (LT) recipients, 90% for acetaminophen overdose spontaneous survivors, and 76% for non-

acetaminophen spontaneous survivors [11]. This positive trend has been attributed to the earlier recognition

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of this condition, the improvement of the intensive care unit (ICU) management, and the developments in

emergent LT [10]. Overall, the most common causes of death in ALF have been multi-organ failure (18%),

liver failure (17%), and sepsis (12%) [11].

PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS

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In ALF, the liver insult results in extensive death of hepatocytes with activation of the innate immune system

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responses (Kupffer cells and circulating monocytes) causing a large production of inflammatory mediators.

The ‘‘spill-over’’ of these inflammatory mediators into the circulation ultimately leads to the systemic

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disturbances and clinical manifestations of ALF [12]. An overwhelming systemic inflammatory response

syndrome (SIRS) is associated with the several organ failures that may ensue.

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In parallel to the pro-inflammatory response, a compensatory anti-inflammatory response develops [13].

Although within the injured liver, the production of anti-inflammatory mediators serves to dampen pro-
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inflammatory responses, limit the extent of tissue injury, and promote liver regeneration, their release into the

systemic circulation is associated with a predisposition to infection [14]. At this stage, circulating monocytes
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may become functionally impaired and less able to respond to infectious stimuli, a state often referred as

imunne paresis [15,16]. Consequently, sepsis and multi-organ failure are frequently the cause of death in
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ALF. A summary of clinical manifestations related to the organ failures that may ensue in the context of ALF

is presented in Table 3.
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GENERAL MANAGEMENT
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The initial management of acute liver injury (hepatitis) or ALF is supportive with the objective to optimize

conditions for the liver to regenerate and prevent and treat as early as possible complications [17]. While

most patients with acute liver injury may be managed in a regular ward, patients with ALF should be referred

to the ICU, ideally one in a center capable of providing emergent LT, as soon as possible as they may

deteriorate quickly [1].

The initial diagnostic approach should be directed at detecting and assessing the severity of hepatitis, HE,

coagulopathy, and other organ failures. Clinical history taking, if possible, may be important to understand

the time between jaundice and HE onset, etiology factors (e.g. alcohol intake, viral infection, drugs,

mushroom, or tisane ingestion), and suspected or known previous liver disease. Physical examination allows

to detect signs of organ failures and should include a mental status evaluation (West-Haven criteria for overt

HE and, if feasible, a neuropsycological test for covert HE) and a search for stigmata of chronic liver disease.

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A list of useful initial laboratory tests is displayed in Table 4. Abdominal imaging with ultrasonography (with

doppler studies) or computed tomography (CT) scan (with intravenous contrast if safe) helps to exclude

features of chronic liver disease and biliary, pancreatic or other intra-abdominal pathology that could be the

origin or contribute to the liver failure. Liver biopsy (transcutaneous or transjugular) should be considered

whenever the etiology remains unclear and histopathology information may help to change management

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decisions, including LT assessment.

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General therapeutic approach

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Hemodynamics

Patients with ALF are often volume depleted at presentation and require fluid resuscitation. As in many other

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hypovolemic syndromes, crystalloids should be the initial fluids of choice, with normal saline (sodium chloride

0.9%) being the most frequently in use [17]. Nevertheless, it may be considered the use of a chloride-
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restrictive solution (e.g Plasma-Lyte 148, Hartmann’s solution) as it has been shown in patients with acute

illness that it may decrease the risk of metabolic acidosis and acute kidney injury (AKI) [18,19]. In a non-ICU
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setting, some of the simplest parameters can be used as targets for the initial fluid replenishment (while

avoiding fluid overload), for example: mean arterial pressure ≥60-65 mmHg, urine output ≥0.5 mL/kg/h, and
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lactate ≤2 mmol/L.

On the contrary, patients with congestive hepatitis (e.g. heart failure) may be fluid overloaded and diuretics
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may help to improve liver function.

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Hepatic encephalopathy

The correction of all factors that may contribute to the acute confusion (e.g. dehydration, infection, and

serum ions derangements) is important for HE treatment. With this objective, sedative medications should be

avoided, except in situations deemed necessary (e.g. agitation, peri endotracheal intubation for progressive

HE). To exclude intracranial pathology, a CT scan needs to be considered. Regular oral or enteral feeding

should be maintained whenever feasible [20]. Lactulose may add to these patients’ transplant-free survival,

but careful should be taken with possible abdominal distension [21]. L-ornithine-L-aspartate has not shown

benefit neither to HE grade nor overall survival [22].

Coagulopathy

In ALF, overall hemostasis as measured by thromboelastography has been shown to be normal by several

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compensatory mechanisms, even in patients with markedly elevated INR [23]. In the absence of active

bleeding or invasive procedure, it is not advisable to correct the INR with fresh frozen plasma, since clinically

significant blood loss is rare and correction obscures trends in the INR, an important marker of prognosis [1].

Nevertheless, vitamin K deficiency may be present in a minority of patients with ALF, thus vitamin K

supplementation may be used at least once [1,24].

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In ALF, bleeding due to fibrinolysis has been found to be limited due to high levels of plasminogen activator

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inhibitor-1 [25]. In the absence of active bleeding or invasive procedure, the platelet count should be

maintained at least above the appropriate spontaneous bleeding threshold.

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Infection

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ALF risk of immune paresis increases susceptibility to infection which may preclude emergent LT. Therefore,

surveillance for infection (including chest radiography and periodic cultures of sputum, urine, and blood)
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should be undertaken, while maintaining a low threshold for starting anti-microbial therapy [1]. Prophylactic

anti-microbials have not been proven to improve 21-day survival in ALF [26]. Nevertheless, the development
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of grade III-IV HE or SIRS has been associated with infection and worse outcomes [27,28].
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Etiology specific therapeutic approach

Acetaminophen
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N-acetylcysteine (NAC) has been largely used as an antidote for acetaminophen intoxication. Its mechanism

of action has to do mainly with glutathione replenishment, a crucial molecule for acetaminophen
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detoxification in the liver [29,30]. In ALF, NAC use has been shown to significantly improve overall survival

with a low rate of side effects [31]. Although reported more effective within 48 hours of acetaminophen

ingestion, NAC is currently being started in many centers when acetaminophen intoxication is suspected

(e.g. reported history of acetaminophen intake outside dose normal range or transaminases ≥3500 IU/L,

especially in an alcohol intake or fasting context), irrespective of acetaminophen dose, time since ingestion,

or acetaminophen serum level because it is often difficult to establish when was the initial drug intake or if

that was a one-time ingestion or a staggered overdose [1,32]. NAC administration protocols are presented in

Table 5.

Non-acetaminophen

In non-acetaminophen related ALF, namely in drug-induced liver injury or hepatitis B, NAC seems to play a

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therapeutic role also as it has been shown to improve transplant-free survival when given during early HE

stages (grade I-II) [33,34]. These results may be related to other effects that have been attributed to NAC, for

example, improving hemodynamics and oxygen use and decreasing the risk of cerebral edema [26,35]. The

mechanism of such effects has not been cleared, but it may involve reducing the production of pro-

inflammatory cytokines (e.g. IL17), scavenging of free radicals, or changes in the hepatic blood flow

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[35,36,37].

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Several ALF etiologies may require specific therapies, for example: (1) consider antiviral therapy for Hepatitis

B virus, Cytomegalovirus, Herpes simplex virus, or Varicella zoster virus related ALF; (2) consider steroid

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therapy for auto-immune hepatitis related ALF; (3) consider penicillin G or silibinin in Amanita phalloides

related ALF; (4) consider emergent delivery for pregnancy related ALF (e.g. acute fatty liver of pregnancy or

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hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome) [1].
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INTENSIVE CARE MANEGEMENT

ALF may lead to several organ failures therefore ICU admission should be considered as early as possible,
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especially when HE is being difficult to control in a regular ward or coagulopathy is progressing. In this

context, supporting organ failures follows the rules of general ICU patients but with some specificities, which
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deserve to be emphasized.
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Acute lung injury

Acute lung injury may occur in patients with ALF, more often at a later stage of their clinical course, namely
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with liver regeneration or sepsis [4]. While patients with acute respiratory distress syndrome (ARDS) may

require greater number of ventilator days, the requirement for vasopressors or renal replacement therapy

(RRT), ICU stay and mortality have been described as similar to patients without ARDS [38].

Management of ARDS in this context, albeit following general intensive care rules, may be more difficult

because increasing positive end-expiratory pressure may exacerbate cerebral edema or liver congestion

[39]. Nevertheless, finding the optimum positive end-expiratory pressure for each patient may help to

improve oxygenation while minimizing such adverse consequences [40,41].

Hemodynamics

Patients with ALF typically present an hyperdynamic circulation characterized by high cardiac output and low

peripheral vascular resistance, a pattern resembling that of sepsis. For patients who continue to have

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hypotension despite volume repletion, noradrenaline is the preferred vasopressor, with or without adjunctive

use of vasopressin or its analogues [42].

Echocardiography or invasive hemodynamic monitoring (e.g. PiCCO, Swan Ganz cathether) should be used

to assess cardiac function and help titrate decisions on the doses of fluids and/or vasopressors. Elevated

troponin levels have been associated with an increase in grade III-IV HE and overall mortality [43].

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Nevertheless, it is unclear whether that represents subclinical myocardial ischaemia or simply reflects

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metabolic stress [44].

Relative adrenal insufficiency may be present and the use of steroids has been associated with a decrease

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in noradrenaline dose and overall mortality [45].

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Acute kidney injury

AKI may develop in up to 70% of patients with ALF and has been associated with worse overall survival [46].
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Hyperphosphataemia develops with AKI if there is impaired liver regeneration and has been associated with

poorer outcomes [47]. AKI is often multifactorial and more common with certain etiologies: ischemic hepatitis,
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acute fatty liver of pregnancy, HELLP syndrome, heat stroke, hepatitis A virus, or drug-induced liver injury

due to acetaminophen, phenytoin, trimethoprim-sulfamethoxazole, or macrolides [48].

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In this context, classic indications for renal replacement therapy initiation also apply, including severe

acidosis, hyperkalemia, anuria and/or fluid overload [49]. Further indications may include: removal of toxic
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substances (e.g. acetaminophen, ammonia), difficult to treat hyponatremia, or difficult to treat hyperthermia

[50,51]. Continuous modes of RRT are preferred over intermittent ones as the latter have been associated
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with increased risk of hemodynamic instability and cerebral edema [52].

Cerebral edema and intracranial hypertension

Cerebral edema incidence in patients with ALF has been decreasing throughout the last decades [10]. This

positive trend may reflect improvements in the preventive care and use of emergent LT [17].

In ALF, astrocyte swelling may result in cytotoxic brain edema which may culminate in tonsillar herniation and

death. Liver-brain pro-inflammatory signaling mechanisms involve the transduction of systemically-derived

cytokines as well as the gliotoxic effects of ammonia and lactate [53].

Frequent neurological examination (including pupils) and the use of transcranial doppler are simple

strategies to monitor for signs of cerebral edema and intracranial pressure. On the contrary, CT findings

compatible with intracranial hypertension often present too late in the course of this condition. Invasive

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monitoring of intracranial pressure has not been shown to improve these patients' hospital survival [54].

Nevertheless, it is still not clear if patients with the highest risk for cerebral edema and intracranial

hypertension (e.g. ammonia >150mmol/L, vasopressors requirement, or RRT requirement) may benefit from

such monitoring capacity [55].

The approach to cerebral edema and intracranial hypertension consists of: (1) head of the bed >30º; (2)

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minimize patient stimulation; (3) sedation and invasive mechanical ventilation; (4) treat fever (while active

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hypothermia has not been proven to prevent cerebral edema and intracranial hypertension) [56,57]; (5) treat

seizures (while prophylaxis has unclear value) [1]; (6) aim for a mean arterial pressure of ≥75mmHg with

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fluids and/or vasopressors, the goal being to maintain an intracranial pressure <25mmHg and a cerebral

perfusion pressure >50mmHg; (7) consider using RRT to promote more effective ammonia clearance [51];

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(8) aim for a serum sodium of 145-155mmol/L with hypertonic saline (3-30% infusion) for prophylaxis in

patients with grade III-IV HE [58]; (9) consider using mannitol (0.5-1g/Kg bolus) to transiently reduce
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intracranial pressure when there is established intracranial hypertension (repeat if serum osmolality

<320mOsm/L) [59]; (10) consider using hyperventilation (aiming for a PCO2 25-30mmHg) in cases of
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established intracranial hypertension despite optimized treatment to try to delay the progression to tonsillar

herniation [60].
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Extracorporeal liver support systems

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The rationale for using an extracorporeal liver support (ECLS) system in ALF is to help maintain homeostasis

while the liver regenerates (e.g. ischemic hepatitis or acetaminophen-related ALF) or until an organ is
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available for transplantation (all etiologies). An ideal ECLS system would be one capable of assisting on 3

major liver functions: removal of toxins, biosynthesis, and immune modulation [61]. However, none of the

artificial (depuration through membranes) or bioartificial (hepatocytes) systems available performs efficiently

all of these functions [62,63].

Two artificial ECLS systems have been studied in ALF with randomized controlled trials: molecular adsorbent

recirculating system (MARS) and high-volume plasmapheresis (HVP). With MARS, blood is dialyzed across

an albumin-impregnated high-flux dialysis membrane (pores with 50kDa) and against a dialysate with

albumin. Subsequently, 2 sequential adsorbent columns containing activated charcoal and anion exchange

resin remove most of the water-soluble and albumin-bound toxins. In a recent study, MARS has not been

proven to improve 6-month survival in ALF [64]. However, a confounder may have been the median listing-

to-transplant time which was only 16 hours, with 75% of enrolled patients undergoing LT within 24 hours.

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With HVP, patients' plasma is replaced by fresh frozen plasma with the objective of removing plasma

cytokines and adhesion molecules, replace plasma factors, and potentially modulate the immune system. In

a recent study, HVP has been shown to significantly improve hospital survival, especially for patients with

contra-indications for LT [65]. Nevertheless, a limitation to account for may have been the 12-year inclusion

period. With both MARS and HVP, side effects have been reported as similar to standard therapy [64,65].

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Several bioartificial ECLS systems have been clinically tested, for example: HepatAssist (Arbios, formerly

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Circe, Waltham, Massachusetts, US), extracorporeal liver support device (ELAD ; Vital Therapies, San
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Diego, California, US), modular extracorporeal liver support system (MELS ; Charit , Berlin, Germany),

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TM
bioartificial liver support system (BLSS ; Excorp Medical, Minneapolis, Minnesota, US), and Amsterdam
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Medical Center bioartificial liver (AMCBAL ; AMC, Amsterdam, The Netherlands) [1]. A meta-analysis has

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shown that these systems failed to improve survival in ALF [66]. Nevertheless, more well designed clinical

trials in humans are likely needed to fully evaluate these systems efficacy and safety [67].
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LIVER TRANSPLANTATION
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LT is the only definitive treatment for patients with ALF. Overall survival after LT has been reported to be

lower for patients with ALF in comparison to patients with cirrhosis until one year after transplant, but it tends
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to be similar from then on [68]. In fact, most deaths after LT for patients with ALF occur from infection during

the first 3 postoperative months [4]. Nevertheless, survival following LT for ALF has been improving
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throughout the last decades, with 21-day survival reaching 96% for the period of 2006 to 2013 [69].

Cadaveric donor LT has been the norm in ALF, but living-donor transplant has been performed in some
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large-volume centers with acceptable outcomes. Despite this, controversy remains in regards to ethical

issues, namely the risk of living-donor coercion and morbidity or mortality [70]. Another strategy to prevent

waitlist mortality has been auxiliary transplantation (partial graft as temporary support for native liver

regeneration), which has shown reasonable outcomes too [71].

In ALF, stratifying patients based on their risk of death without LT is crucial in order to prioritize them for

transplantation. King's College criteria have been used worldwide for this purpose (Table 6) [72]. A recent

meta-analysis has revealed its prognostic ability in comparison with the MELD score: for acetaminophen-

related ALF, sensitivities were 58% and 80%, respectively, and specificities were 89% and 53%, respectively;

for non-acetaminophen etiologies, sensitivities were 58% and 76%, respectively, and specificities were 74%

and 73%, respectively [73]. Therefore, King's College criteria remain highly specific for acetaminophen-

related ALF, but less accurate for non-acetaminophen etiologies. Another useful tool for prognostication of

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death without LT in patients with hepatitis B-related ALF and grade III-IV HE may be the Clichy criteria.

According to this tool, a serum factor V level of <20% in patients aged ≤30 years or <30% in any other

patients prognosticates mortality with a positive predictive value of 82% and a negative predictive value of

98% [74]. However, it has been shown that the Clichy criteria perform worse than the King's College criteria

overall [75].

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Risk stratification in ALF may be improved further if taking into account not only the probability of death

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without LT, but also the probability of death after transplantation. Studies have suggested that some

characteristics were associated with an increased risk of death after LT: male recipient, recipient aged >45

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years, recipient on vasopressors, ABO incompatible transplant, and high-risk graft use [76,77].

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CONCLUSIONS

ALF diagnostic and therapeutic strategies have evolved throughout the time and that has been associated
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with improved outcomes. New advances in basic and clinical research may potentiate even more such

outcomes. Despite this, these patients' early referral to an LT center, ICU timely treatment, and a
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comprehensive multidisciplinary strategy in risk stratification and selection for LT will continue to be

fundamental steps for a successful approach.

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REFERENCES

[1] Lee W, Larson AM, Stravitz RT. AASLD Position Paper: The Management of Acute Liver Failure: Update

2011. [Link]

[2] O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;

342(8866):273-5.

P T
[3] Ostapowicz G, Fontana RJ, Schiødt FV, Larson A, Davern TJ, Han SH et al. Results of a prospective

RI
study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137(12):947-

54.

SC
[4] Bernal W, Wendon J. Acute liver failure. N Engl J Med 2013; 369:2525-34.

[5] Acharya SK, Batra Y, Hazari S, Choudhury V, Panda SK, Dattagupta S. Etiopathogenesis of acute hepatic

NU
failure: Eastern versus Western countries. J Gastroenterol Hepatol 2002; 17 Suppl 3:S268-73.

[6] Gulmez SE, Larrey D, Pageaux GP, Bernuau J, Bissoli F, Horsmans Y et al. Liver transplant associated
MA
with paracetamol overdose: results from the seven-country SALT study. Br J Clin Pharmacol 2015;

80(3):599-606.
ED

[7] Hadem J, Tacke F, Bruns T, Langgartner J, Strnad P, Denk GU et al. Etiologies and outcomes of acute

liver failure in Germany. Clin Gastroenterol Hepatol 2012; 10(6):664-9.

PT

[8] Areia M, Romãozinho JM, Ferreira M, Amaro P, Leitão MC. Fulminant hepatic failure: a Portuguese

experience. Eur J Gastroenterol Hepatol 2007; 19(8):665-9.

CE

[9] Bernal W, Auzinger G, Dhawan A, Wendon J. Acute liver failure. Lancet 2010; 376(9736):190-201.

[10] Bernal W, Hyyrylainen A, Gera A, Audimoolam VK, McPhail MJ, Auzinger G et al. Lessons from look-
AC

back in acute liver failure? A single centre experience of 3300 patients. J Hepatol 2013; 59(1):74-80.

[11] Fontana RJ, Ellerbe C, Durkalski VE, Rangnekar A, Reddy RK, Stravitz T et al. Two-year outcomes in

initial survivors with acute liver failure: results from a prospective, multicentre study. Liver Int 2015;

35(2):370-80.

[12] Possamai LA, Thursz MR, Wendon JA, Antoniades CG. Modulation of monocyte/macrophage function: a

therapeutic strategy in the treatment of acute liver failure. J Hepatol 2014; 61(2):439-45.

[13] Antoniades C, Berry P, Wendon J, Vergani D. The importance of immune dysfunction in determining

outcome in acute liver failure. J Hepatol 2008; 49:845-61.

[14] Antoniades CG, Quaglia A, Taams LS, Mitry RR, Hussain M, Abeles R et al. Source and characterization

of hepatic macrophages in acetaminophen- induced acute liver failure in humans. Hepatology 2012; 56:735-

46.

12
 ACCEPTED MANUSCRIPT
[15] Antoniades CG, Khamri W, Abeles RD, Taams LS, Triantafyllou E, Possamai LA et al. Secretory

leukocyte protease inhibitor: A pivotal mediator of anti- inflammatory responses in acetaminophen induced

acute liver failure. Hepatology 2014; 59:1564-76.

[16] Antoniades CG, Berry PA, Davies ET, Hussain M, Bernal W, Vergani D et al. Reduced monocyte HLA-

DR expression: a novel biomarker of disease severity and outcome in acetaminophen-induced acute liver

P T
failure. Hepatology 2006; 44:34-43.

RI
[17] Bernal W, Lee WM, Wendon J, Larsen FS, Williams R. Acute liver failure: A curable disease by 2024? J

Hepatol 2015; 62(1 Suppl):S112-20.

SC
[18] Yunos MN, Bellomo R, Hegarty C, Story D, Ho L, Bailey M. Association Between a Chloride-Liberal vs

Chloride-Restrictive Intravenous Fluid Administration Strategy and Kidney Injury in Critically Ill Adults. JAMA

NU
2012; 308(15):1566-72.

[19] Raghunathan K, Murray PT, Beattie WS, Lobo DN, Myburgh J, Sladen R et al. Choice of fluid in acute
MA
illness: what should be given? An international consensus. Br J Anaesth 2014; 113(5):772-83.

[20] Plauth M, Cabré E, Riggio O, Assis-Camilo M, Pirlich M, Kondrup J et al. ESPEN Guidelines on Enteral
ED

Nutrition: Liver disease. Clin Nutr 2006; 25(2):285-94.

[21] Alba L, Hay JE, Angulo P, Lee WM. Lactulose therapy in acute liver failure. J Hepatol 2002; 36:33A.
PT

[22] Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute

liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology 2009; 136(7):2159-68.

CE

[23] Stravitz RT, Lisman T, Luketic VA, Sterling RK, Puri P, Fuchs M et al. Minimal effects of acute liver injury/

acute liver failure on hemostasis as assessed by thromboelastography. J Hepatol 2012; 56(1):129-36.

AC

[24] Pereira SP, Rowbotham D, Fitt S, Shearer MJ, Wendon J, Williams R. Pharmacokinetics and efficacy of

oral versus intravenous mixed-micellar phylloquinone (vitamin K1) in severe acute liver disease. J Hepatol

2005; 42:365-70.

[25] Pernambuco JR, Langley PG, Hughes RD, Izumi S, Williams R. Activation of the fibrinolytic system in

patients with fulminant liver failure. Hepatology 1993; 18(6):1350-6.

[26] Karvellas CJ, Cavazos J, Battenhouse H, Durkalski V, Balko J, Sanders C et al. Effects of antimicrobial

prophylaxis and blood stream infections in patients with acute liver failure: a retrospective cohort study. Clin

Gastroenterol Hepatol 2014; 12(11):1942-9.

[27] Vaquero J, Polson J, Chung C, Helenowski I, Schiodt FV, Reisch J et al. Infection and the progression of

encephalopathy in acute liver failure. Gastroenterology 2003; 125:755-64.

[28] Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R. The systemic inflammatory

13
 ACCEPTED MANUSCRIPT
response syndrome in acute liver failure. Hepatology 2000; 32:734-39.

[29] Saito C, Zwingmann C, Jaeschke H. Novel mechanisms of protection against acetaminophen

hepatotoxicity in mice by glutathione and N-acetylcysteine. Hepatology 2010; 51(1):246-54.

[30] Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008; 359:285-92.

[31] Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ et al. Intravenous acetylcysteine in

P T
paracetamol induced fulminant hepatic failure: a prospective controlled trial. BMJ 1991; 303(6809):1026-9.

RI
[32] Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of

alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995; 22(3):767-73.

SC
[33] Singh S, Hynan LS, Lee WM; Acute Liver Failure Study Group. Improvements in hepatic serological

biomarkers are associated with clinical benefit of intravenous N-acetylcysteine in early stage non-

NU
acetaminophen acute liver failure. Dig Dis Sci 2013; 58(5):1397-402.

[34] Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM et al. Intravenous N-acetylcysteine
MA
improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology

2009; 137(3):856-64.
ED

[35] Harrison PM, Wendon JA, Gimson AES, Alexander GJM, Williams R. Improvement by acetylcysteine of

hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991; 324:1852–7.
PT

[36] Stravitz RT, Sanyal AJ, Reisch J, Bajaj JS, Mirshahi F, Cheng J et al. Effects of N-acetylcysteine on

cytokines in non-acetaminophen acute liver failure: potential mechanism of improvement in transplant-free

CE

survival. Liver Int 2013; 33(9):1324-31.

[37] Jones AL. Mechanism of action and value of N-acetylcysteine in the treatment of early and late
AC

acetaminophen poisoning: a critical review. J Toxicol Clin Toxicol 1998; 36:277-85.

[38] Audimoolam VK, McPhail MJ, Wendon JA, Willars C, Bernal W, Desal SR et al. Lung injury and its

prognostic significance in acute liver failure. Crit Care Med 2014; 42(3):592-600.

[39] Sass DA, Shakil AO. Fulminant hepatic failure. Liver Transpl 2005; 11(6):594-605.

[40] Suter PM, Fairley B, Isenberg MD. Optimum end-expiratory airway pressure in patients with acute

pulmonary failure. N Engl J Med 1975; 292(6):284-9.

[41] Mascia L, Grasso S, Fiore T, Bruno F, Berardino M, Ducati A. Cerebro-pulmonary interactions during the

application of low levels of positive end-expiratory pressure. Intensive Care Med 2005; 31(3):373-9.

[42] Eefsen M, Dethloff T, Frederiksen H-J, Hauerberg J, Hansen BA, Larsen FS. Comparison of terlipressin

and noradrenalin on cerebral perfusion, intracranial pressure and cerebral extracellular concentrations of

lactate and pyruvate in patients with acute liver failure in need of inotropic support. J Hepatol 2007; 47:381-6.

14
 ACCEPTED MANUSCRIPT
[43] Parekh NK, Hynan LS, De Lemos J, Lee WM; Acute Liver Failure Study Group. Elevated troponin I

levels in acute liver failure: is myocardial injury an integral part of acute liver failure? Hepatology 2007;

45(6):1489-95.

[44] Audimoolam VK, McPhail MJ, Sherwood R, Willars C, Bernal W, Wendon JA et al. Elevated troponin I

and its prognostic significance in acute liver failure. Crit Care 2012; 16(6):R228.

P T
[45] Marik PE, Gayowski T, Starzl TE; Hepatic Cortisol Research and Adrenal Pathophysiology Study Group.

RI
The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit Care Med 2005;

33(6):1254-9.

SC
[45] Tujios SR, Hynan LS, Vazquez MA, Larson AM, Seremba E, Sanders CM et al. Risk factors and

outcomes of acute kidney injury in patients with acute liver failure. Clin Gastroenterol Hepatol 2015;

NU
13(2):352-9.

[47] Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-
MA
induced hepatotoxicity. Hepatology 2002; 36:659-65.

[48] Urrunaga NH, Magder LS, Weir MR, Rockey DC, Mindikoglu AL. Prevalence, Severity, and Impact of
ED

Renal Dysfunction in Acute Liver Failure on the US Liver Transplant Waiting List. Dig Dis Sci 2016;

61(1):309-16.
PT

[49] Bagshaw SM, Wald R. Acute kidney injury: Timing of renal replacement therapy in AKI. Nat Rev Nephrol

2016; 12(8):445-6.
CE

[50] Gosselin S, Juurlink DN, Kielstein JT, Ghannoum M, Lavergne V, Nolin TD et al. Extracorporeal

treatment for acetaminophen poisoning: recommendations from the EXTRIP workgroup. Clin Toxicol (Phila)
AC

2014; 52(8):856-67.

[51] Slack AJ, Auzinger G, Willars C, Dew T, Musto R, Corsilli D et al. Ammonia clearance with

haemofiltration in adults with liver disease. Liver Int 2014; 34(1):42-8.

[52] Davenport A, Will EJ, Davidson AM. Improved cardiovascular stability during continuous modes of renal

replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med 1993; 21:328-

38.

[53] Butterworth RF. Pathogenesis of Hepatic Encephalopathy and Brain Edema in Acute Liver Failure. J Clin

Exp Hepatol 2015; 5:S96-S103.

[54] Karvellas CJ, Fix OK, Battenhouse H, Durkalski V, Sanders C, Lee WM et al. Outcomes and

complications of intracranial pressure monitoring in acute liver failure: a retrospective cohort study. Crit Care

Med 2014; 42(5):1157-67.

15
 ACCEPTED MANUSCRIPT
[55] Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial Ammonia and Clinical Risk

Factors forEncephalopathy and Intracranial Hypertension in Acute Liver Failure. Hepatology 2007;

46(6):1844-52.

[56] Bernal W, Murphy N, Brown S, Whitehouse T, Bjerring PN, Hauerberg J et al. A multicentre randomized

controlled trial of moderate hypothermia to prevent intracranial hypertension in acute liver failure. J Hepatol

P T
2016; pii: S0168-8278(16)30030-7.

RI
[57] Karvellas CJ, Todd Stravitz R, Battenhouse H, Lee WM, Schilsky ML; US Acute Liver Failure Study

Group. Therapeutic hypothermia in acute liver failure: a multicenter retrospective cohort analysis. Liver

SC
Transpl 2015; 21(1):4-12.

[58] Murphy N, Auzinger G, Bernal W, Wendon J. The effect of hypertonic sodium chloride on intracranial

NU
pressure in patients with acute liver failure. Hepatology 2002; 39:464-70.

[59] Canalese J, Gimson AE, Davis C, Mellon PJ, Davis M, Williams R. Controlled trial of dexamethasone
MA
and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982; 23(7):625-9.

[60] Ede RJ, Gimson AE, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral
ED

oedema in fulminant hepatic failure. J Hepatol 1986; 2:43-51.

[61] Karvellas CJ, Subramanian RM. Current Evidence for Extracorporeal Liver Support Systems in Acute
PT

Liver Failure and Acute-on-Chronic Liver Failure. Crit Care Clin 2016; 32(3):439-51.

[62] Khuroo MS, Khuroo MS, Farahat KL. Molecular adsorbent recirculating system for acute and acute-on-
CE

chronic liver failure: a meta-analysis. Liver Transpl 2004; 10(9):1099-106.

[63] Karvellas CJ, Gibney N, Kutsogiannis D, Wendon J, Bain VG. Bench-to-bedside review: current
AC

evidence for extracorporeal albumin dialysis systems in liver failure. Crit Care 2007; 11(3):215.

[64] Saliba F, Camus C, Durand F, Mathurin P, Letierce A, Delafosse B 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; 159(8):522-31.

[65] Larsen FS, Schmidt LE, Bernsmeier C, Rasmussen A, Isoniemi H, Patel VC et al. High-volume plasma

exchange in patients with acute liver failure: An open randomised controlled trial. J Hepatol 2016; 64(1):69-

78.

[66] Kjaergard LL, Liu J, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for acute and

acute-on-chronic liver failure: a systematic review. JAMA 2003; 289(2):217-22.

[67] Lee KC, Stadlbauer V, Jalan R. Extracorporeal liver support devices for listed patients. Liver Transpl

2016; 22(6):839-48.

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[68] Berg CL, Steffick DE, Edwards EB, Heimbach JK, Magee JC, Washburn WK et al. Liver and intestine

transplantation in the United States 1998-2007. Am J Transplant; 9(4 Pt 2):907-31.

[69] Reuben A, Tillman H, Fontana RJ, Davern T, McGuire B, Stravitz RT et al. Outcomes in Adults With

Acute Liver Failure Between 1998 and 2013: An Observational Cohort Study. Ann Intern Med 2016;

164(11):724-32.

P T
[70] Brown RS Jr, Russo MW, Lai M, Shiffman ML, Richardson MC, Everhart JE et al. A survey of liver

RI
transplantation from living adult donors in the United States. N Engl J Med 2003; 348(9):818-25.

[71] van Hoek B, de Boer J, Boudjema K, Williams R, Corsmit O, Terpstra OT. Auxiliary versus orthotopic

SC
liver transplantation for acute liver failure. EURALT Study Group. European Auxiliary Liver Transplant

Registry. J Hepatol 1999; 30:699-705.

NU
[72] O’Grady JG, Alexander GJM, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic

failure. Gastroenterology 1989; 97:439-55.

MA
[73] McPhail MJ, Farne H, Senvar N, Wendon JA, Bernal W. Ability of King's College Criteria and Model for

End-Stage Liver Disease Scores to Predict Mortality of Patients With Acute Liver Failure: A Meta-analysis.
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Clin Gastroenterol Hepatol; 14(4):516-25.

[74] Bismuth, Samuel D, Gugenheim J, Castaing D, Bernuau J, Rueff B et al. Emergency liver
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transplantation for fulminant hepatitis. Ann Intern Med 1987; 107:337-41.

[75] Pauwels A, Mostefa-Kara N, Florent C, Lévy VG. Emergency liver transplantation for acute liver failure.
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Evaluation of London and Clichy criteria. J Hepatol 1993; 17(1):124-7.

[76] Bernal W, Cross TJ, Auzinger G, Sizer E, Heneghan MA, Bowles M et al. Outcome after wait-listing for
AC

emergency liver transplantation in acute liver failure: a single centre experience. J Hepatol 2009; 50(2):306-

13.

[77] Germani G, Theocharidou E, Adam R, Karam V, Wendon J, O'Grady J et al. Liver transplantation for

acute liver failure in Europe: outcomes over 20 years from the ELTR database. J Hepatol 2012; 57(2):288-

96.

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Table 1. Acute liver failure phenotypes.

Hyperacute (within 7 days) Acute (8 to 28 days) Subacute (5 to 26 weeks)

Etiology example Acetaminophen DILI, hepatitis Hepatitis B Non-acetaminophen DILI
A/E
Transaminases +++ ++ +

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Bilirubin + ++ +++

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INR +++ ++ +
Cerebral edema High risk High risk Low risk

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Survival without LT High Intermediate Low
DILI: drug-induced liver injury. INR: international normalized ratio. LT: liver transplantation.

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Table 2. Acute liver failure etiologies.

Viruses
Hepatitis A, B, D or E viruses
Cytomegalovirus
Epstein-Barr virus

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Herpes simplex virus

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Varicella zoster virus

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Parvovirus
Drug-induced liver injury
Acetaminophen

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Non-acetaminophen (e.g. isoniazid, phenytoin, valproate, propylthiouracil, nitrofurantoin)
Recreational drugs (e.g. cocaine, MDMA)
Autoimmune hepatitis

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Ischemic/congestive hepatitis
Budd-Chiari syndrome
Wilson’s disease
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Amanita phalloides
Pregnancy (e.g. acute fatty liver of pregnancy, HELLP syndrome)
Heat stroke
Malignant infiltration
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Seronegative (indeterminate)
MDMA: 3,4-methylenedioxy-N-methylamphetamine. HELLP: hemolysis, elevated liver enzymes, and low platelets.
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Table 3. Acute liver failure organ failures.

Organ failure Pathophysiology

Liver Hyperlactatemia: decreased lactate clearance
Hyperammonemia: decreased ammonia clearance
Coagulopathy: decreased synthesis of pro- and anticoagulant factors

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Hypoglycemia: decreased gluconeogenesis

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Portal hypertension: may develop especially in subacute disease

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Brain Hepatic encephalopathy: circulating inflammatory mediators and hyperammonemia
Cerebral edema: inflammatory mediators from microglial cells and glutamine accumulation in astrocytes
Cardiovascular Hypotension or shock especially if sepsis superimposes

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Lungs Acute lung injury or acute respiratory distress syndrome: SIRS, sepsis and/or fluid overload
Kidneys Acute kidney injury: SIRS, sepsis and/or hypovolemia
Pancreas Acute pancreatitis: SIRS and/or drug toxicity (e.g. acetaminophen)

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Multi-organ failure SIRS or sepsis (imunne paresis)
SIRS: systemic inflammatory response syndrome.
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Table 4. Initial laboratory tests for acute liver injury or acute liver failure.

Assessment Test
Severity Arterial blood gas
(serum) Arterial lactate
Arterial ammonia

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Hemoglobin, leucocytes, platelets

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INR, aPTT, fibrinogen, factor V

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AST, ALT, bilirubin, albumin, alkaline phosphatase, LDH, amylase
Creatinine, urea, sodium, chloride, potassium, calcium, magnesium, phosphorus, creatine kinase
Etiology HAV IgM, HBsAg, HBc IgM, Anti HCV, Anti HEV, CMV IgM, EBV IgM, HSV IgM, VZV IgM, Anti HIV

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(serum or urine) Ceruloplasmin, copper
Anti-nuclear antibody, anti-smooth-muscle antibody, immunoglobulins
Acetaminophen, toxicology screen

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Blood type
Pregnancy test (females)
INR: international normalized ratio. aPTT: activated partial thromboplastin time. AST: asparte aminotransferase. ALT: alanine
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aminotransferase. LDH: lactate dehydrogenase. HAV: hepatitis A virus. HBs: hepatitis B virus surface antigen. HBc: hepatitis B virus
core antibody. HCV: hepatitis C virus. HEV: hepatitis E virus. CMV: cytomegalovirus. EBV: Epstein-Barr virus. HSV: Herpes simplex
virus. VZV: Varicella zoster virus. HIV: human immunodeficiency virus.
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Table 5. N-acetylcysteine protocols in acute liver failure.

Route and dosage [1,2]

Oral or enteral Loading dose of 140 mg/kg in glucose 5%, followed by 70 mg/kg in glucose 5% q 4 h x 17 doses (overall 72h).
Intravenous Loading dose of 150mg/Kg in glucose 5% for 15 minutes, followed by 50mg/kg in glucose 5% for 4 hours, and
followed by 100mg/Kg in glucose 5% for 16 hours (overall 20 hours).
Length of therapy [1,2]

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Controversy exists but at least a 72h hour period irrespective of route has been suggested. A decision to stop based on consistent

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clinical improvement of patients has also been suggested.
More frequent adverse effects [1,2]

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Nausea, vomiting, flushing, rash, dyspnea, tachycardia, edema, anaphylactoid reaction
[1] Lee W, Larson AM, Stravitz RT. AASLD Position Paper: The Management of Acute Liver Failure: Update 2011.
[Link]

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[2] Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med 2008; 359:285-92.

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Table 6. King's College criteria in acute liver failure.

Acetaminophen-related acute liver failure Non-acetaminophen-related acute liver failure

A) Single criterion: A) Single criterion:
- pH <7.30 or lactate >3.0mmol/L after adequate - INR >6.5
fluid ressuscitation

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B) Three criteria: B) Three of 5 criteria:

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- Grade III-IV (West-Haven) hepatic encephalopathy - Age <10 or >40 years
- INR >6.5 - Time from jaundice to coma >7 days

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- Creatinine >3.4mg/dL - INR >3.5
- Bilirubin >17mg/dL

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- Unfavourable etiology: drug-induced liver injury,
Wilson’s disease, or seronegative liver injury

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HIGHLIGHTS

- Outcomes of patients with acute liver failure have been improving, but morbidity and mortality are still

of concern.

- Earlier recognition and referral to the intensive care unit have been important to improve these

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patients’ outcomes.

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- Intensive care management should take into consideration hepatic encephalopathy, cerebral edema

and intracranial hypertension, hemodynamics, acute kidney injury, coagulopathy, and infection.

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- Selection of patients for liver transplantation has been based on prognostic scores (e.g. Kings’

College criteria) but limitations may apply.

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