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27. Acute liver failure
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Recent data indicates that high-density lipoprotein (HDL) could be
a marker for the severity of ALF (Etogo-Asse 2012). Data in ALF patients
regarding lipid-associated parameters is limited, but HDL and cholesterol
seem to be important for liver cell regeneration. In patients with ALF,
HDL was suppressed, correlated with serum ALT levels, and was lower
in patients without spontaneous remission (i.e., deceased or requiring
transplantation) (Manka 2014). However, further studies are required to
conirm which mechanisms play a role and what efects can be expected.
More recently it was shown that liver biopsy by laparoscopy can assist in
prognosis of ALF course and outcome, as immunohistochemical assessment
of regeneration (i.e., KI67) and cell death (M30) become available (Dechêne
2014).
Table 3. Grade of hepatic encephalopathy (West Haven criteria)
Grade Clinical findings Asterixis EEG
I Changes in behavior, euphoria,
depression, mild confusion
II Inappropriate behavior, lethargy,
moderate confusion
III Marked confusion, somnolence + Triphasic waves
IV Coma – Delta waves
+/– Triphasic waves
+ Triphasic waves
Prognosis
With persistently high, although variable, mortality rates from ten to
ninety percent, accurate prediction of the clinica l course is cr ucial for accurate
management and decision-making. Most importantly, identiication of the
underlying aetiology improves prognosis and opens the door for speciic
treatment. The degree of hepatic encephalopathy is traditionally considered
an important indicator of prognosis (O’Grady 1989). Cerebral oedema
and renal failure worsen the prognosis dramatically. In some studies, the
IN was determined as the strongest single parameter in predicting the
prognosis of ALF. Another interesting point is that the presence of hepatic
encephalopathy means a poor prognosis for acetaminophen-induced ALF,
which in contrast has little meaning for amanita mushroom poisoning.
Liver transplantation is the last treatment option in patients with ALF,
when conservative treatment options fail and a lethal outcome is imminent.
Therefore, assessment of likelihood of the individual patient to undergo a
fatal course is important for timely listing of the patient. Standardised
prognosis scores based on reproducible criteria are important in times of
donor organ shortage and to avoid liver transplantation in patients that
might fully recover without liver transplantation (Canbay 2011).
King’s College criteria (KCC) were established in the 1990s based on
indings from a cohort of 588 patients with ALF (O’Grady 1989). The authors
also introduced a classiication based on the onset of encephalopathy ater an
initial rise in bilirubin levels into hyperacute (<7 days), acute (8–28 days) and
subacute (5–12 weeks) liver failure (O’Grady 1993). KCC includes assessment
of encephalopathy, coagulopathy (INR), acid homeostasis (pH), bilirubin
and age. For patients with acetaminophen-induced ALF, a KCC formula was
implied, deviating from that in patients with non-acetaminophen-induced
liver injury. Clichy criteria were introduced for patients with fulmi nant HBV
infection and include the degree of encephalopathy and factor V fraction
as a measure for hepatic synthesis (Bernuau 1986). The model for end stage
liver disease (MELD) was designed to predict the likelihood of survival ater
transjugular portacaval shunt (TIPS) in cirrhotic patients. However, it has
recently been established as an allocation tool for liver transplantation in
patients with cirrhosis in the US and Europe. It was tested as a model for
prediction of ALF and was found to be superior to KCC and Clichy criteria
in independent studies (Schmidt 2007, Yantorno 2007). Novel approaches
that include mechanistic characteristics of ALF like the CK-18 modiied
MELD, which includes novel markers for hepatocellular death or lactate
are promising, but need validation in prospective cohorts (Bechmann
2010, Hadem 2008, utherford 2012). In a recent, large, prospective
study, a prognostic model was developed using dynamic changes of four
independent variables (atrial ammonia, INR, serum bilirubin, hepatic
encephalopathy) over three days, to predict mortality (Kumar 2012).
Recently an association of thyroid hormone status and outcome of ALF has
been demonstrated. Since thyroid hormones are involved in hepatocellular
regeneration, thyroid status might be useful as early indicator for severity
of ALF (Anastasiou 2015).
720 721
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Table 4. Scoring systems in patients with ALF for emergency liver transplantation
Scoring System Prognostic factors
King’s College
Criteria (KCC)
Clichy Criteria HBV Hepatic encephalopathy grade 3–4 and factor V
MELD 10 x [0.957 x In(serum creatinine) + 0.378 x In(total
CK-18 modified
MELD
Bilirubinlactateaetiology score
(BILE score)
ALFSG Index Coma grade, bilirubin, INR, phosphorus, log
ALFED Model Dynamic of variables over 3 days: HE 0–2 points;
Adapted from Canbay 2011; INR, International Normalized Ratio; MELD, model of end stage
liver disease
Paracetamol
intoxication
Nonparacetamol
Arterial pH <7.3 or INR >6.5 and creatinine >300
μmol/L and hepatic encephalapathy grade 3–4
INR >6.5 and hepatic encephalapathy or INR >3.5
and any of these three: bilirubin >300 μmol/L, age
>40 years, unfavourable aetiology (undetermined or
drug-induced)
<20% (for <30 years old); <30% (for >30 years old)
bilirubin) +1.12 x In(INR+0.643)]
10 x [0.957 x In(serum creatinine) + 0.378 x In(CK18/
M65) + 1.12 x In(INR + 0.643)]
Bilirubin (μmol/L)/100 + Lactate (mmol/L) + 4 (for
cryptogenic ALF, Budd-Chiari or Phenprocoumon
induced) –2 (for acetaminophen-induced) +0 (for
other causes)
M30
10
INR 0–1 point; arterial ammonia 0–2 points; serum
bilirubin 0–1 point
Treatment
General management
serology, coeruloplasmin, urine copper concentration, etc.), transjugular
or laparoscopic liver biopsy might be indicated to identify the underlying
disease (Canbay 2011).
Hepatic encephalopathy
In general in patients with hepatic encephalopathy, sedative
agents should be avoided and if necessary restricted to short-acting
benzodiazepines or propofol, as it might decrease intracranial pressure
(Wijdicks 2002). Some studies favour utilisation of ICP monitoring,
especially in patients with hepatic encephalopathy grade III/IV, and
clinical signs of brain oedema. Mannitol therapy (0.5–1 g/kg) might be
beneicial in some patients. Head elevation, induction of hypothermia
and hyperventilation are recommended by some experts in patients with
increased ICP. With worsening of brain oedema, patients present with
systemic hypertension and bradycardia (Cushing relex), dilated and ixed
pupils, and in the end respiratory arrest. The target ICP should remain
below 20 mmHg, with cerebral perfusion pressure above 70 mmHg and
jugular venous saturation of 55 to 80%. Phenytoin is the drug of choice for
treatment of seizures and hypertonic sodium chloride might be beneicial
on ICP (Larsen 2011). Symptomatic treatment of encephalopathy includes
bowel decontamination with neomycin or rifaximin, induction of diarrhoea
and reduction of colonic pH and thus reduction of ammonia absorption by
lactulose as well as treatment with branched-chain aminoacids to improve
peripheral ammonia metabolism, although large, randomised clinical
trials have failed to show clinical improvement (Larson 2010, Nguyen 2011).
Given the high risk of deterioration and development of hepatic
coma, immediate transfer of the patient presenting with ALF to the ICU
is mandatory. Early referral or at least consultation of an experienced
transplant centre is indicated in any ALF patient, since liver transplantation
is the ultimate treatment for ALF in case conservative therapy fails. The
cause of ALF should be determined as soon as possible. Besides speciic
detailed history taking, laboratory and radiologic tests need to be done
in order to establish the diagnosis of ALF and identify the underlying
cause. Diagnostic studies include, but are not limited to, arterial blood
gas analysis, glucose, electrolytes, bilirubin, ammoniac, lactate, protein,
albumin, C-reactive protein (CRP), procalcitonin (PCT), urine electrolytes,
urinalysis, and chest X-ray, cranial computed tomography (CT) in patients
with advanced hepatic encephalopathy as well as assessment of intracranial
pressure (ICP) in some cases. Beyond speciic diagnostic studies (HBV
722 723
Coagulopathy
In general, without clinical signs of bleeding coagulation factor treatment
is not indicated. To exclude vitami n K deiciency, v itamin K challenge should
be performed. Platelets and recombinant activated factor VII are indicated
in case of bleeding or before invasive procedures. Interestingly, in ALF
patients with impaired coagulation according to conventional testing (INR)
may not be at risk for bleeding in laparoscopic procedures (Dechêne 2014).
Liver transplantation
Liver transplantation is the therapy of choice for ALF in those
individuals with insuicient regeneration capacity and an otherwise fatal
27. Acute liver failure
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prognosis. In patients without contraindications to liver transplantation,
the one-year survival rate is as high as 80–90% with a ive-year survival
of 55%. As mentioned above, with liver transplantation available as the
most favourable therapy, the accurate assessment of the patient’s prognosis
is crucial to initiate evaluation of the patient for liver transplantation and
decision making in this clinical setting. The underlying disease, the clinical
condition and the status of the grat inluence the patient’s prognosis
ater the transplant. In times of general organ shortage, the grat pool
might be extended by using living-donor transplants, split liver surgery or
transplantation of livers in reduced conditions (Canbay 2011).
Extracorporal liver support systems
Extracorporal systems include support devices or bioreactors, which
provide individual or a combination of functions that are insuiciently
performed by the diseased liver. The scientiic and clinical aim of the
introduction of these novel techniques is to stabilise the patient until a
donor organ is available or ideally until the liver completely recovers.
However, adequately powered, randomised studies to establish these
techniques in the treatment of ALF are either lacking or have failed to show
any beneit over conventional therapy. Thus, treatment with these devices
most likely remains a part of a bridging-to-transplantation strategy within
an academic setting. The same accounts for novel stem cell and adult
hepatocyte transplant approaches (Canbay 2011).
Mushroom poisoning
Silibinin, with its cytoprotective afects against amanita toxin is used
despite a lack of the controlled trials (Broussard 2001, Ganzert 2008).
Acute HBV infection
Antiviral therapy with lamivudine or entecavir has proven eicient and
safe in fulminant HBV infection (Tillmann 2006). Moreover, with initiation
of entecavir within the irst days of admission, HBsAg concentrations and
cell death were signiicantly reduced (Jochum 2009).
Pregnancy related
Immediate delivery and abortion are the available causal treatments.
With early delivery, the rates of foetal death remain high; however the
mortality rate of the mother decreases signiicantly (Westbrook 2010).
Autoimmune hepatitis
Steroid treatment should be initiated and if started in time might help
to avoid the need for liver transplantation. With improvement of liver
function, prednisone might be tapered and azathioprine treatment added
to the regimens. Recent studies identiied the topical steroid budesonide as
a potential substitute for systemic prednisone therapy (Schramm 2010).
Specific treatment options
Acetaminophen poisoning
Activated oral charcoal (1 g/kg) might be indicated if administered up
to four hours ater acetaminophen ingestion. N-acetyl cysteine infusion
to restore glutathione should be administered until as late as 24 to 36
hours ater ingestion, and continued for 20 hours or longer. Monitoring of
blood acetaminophen levels might help in decision-making regarding the
duration or initiation of treatment. N-acetyl cysteine should be started as
soon as possible, even in patients with a low probability of acetaminophen
overdose or even in patients with non-paracetamol drug-induced ALF (Lee
2009). Steroid and ursodeoxycholic acid combination seems to be efective
in drug-induced severe liver injury (Wree 2011).
724 725
Table 5. Specific treatments for the causes of ALF
Causes Medication Doses
Acetaminophen Activated oral charcoal 1 g/kg
N-acetyl cysteine
(oral/IV )
Mushroom Silibinin 20–50 mg/kg/day
Acute HBV Lamivudine 100–300 mg/day
Entecavir 0.5–1 mg/day
Tenofovir 245 mg/day
Pregnancy Delivery
Autoimmune Prednisolone 1–2 mg/kg/day
Budd-Chiari syndrome TIPS/surgical shunt
HSV Acyclovir 3 x 10 mg/kg/day
150 mg/kg loading dose,
50 mg/kg for 4h,
100 mg/kg for 20h
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HEPATOLOGY
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A clinical textbook
Mauss, Berg, Rockstroh, Sarrazin, Wedemeyer
The tenth edition of Hepatology – A clinical textbook
offers an update of all relevant areas and is a source
of information for physicians, residents and advanced
medical students seeking a broader understanding of
liver disease.
www.hepatologytextbook.com
10th Edition 2020
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