3

Liver transplantation for acute liver failure

John OGrady, MD, FRCPI, Consultant Hepatologist
*
Institute of Liver Studies, Kings College Hospital, Denmark Hill, London SE5 9RS, UK
Keywords:
Encephalopathy
Auxiliary transplantation
Prognostic models
Outcomes
Liver transplantation is now an integral part of the management of
acute liver failure. The challenge for clinicians is to select the
appropriate candidates with a combination of need and high
likelihood of beneting from the transplant. This is achieved
through a combination of prognostic modelling and ongoing
clinical evaluation. Although the outcomes after liver trans-
plantation are good the survival rates do not quite match those
achieved after elective transplantation.
2012 Published by Elsevier Ltd.
Introduction
It is frequently stated that liver transplantation is the only effective treatment for acute liver failure.
This clich fails on two grounds; rstly, it does not acknowledge the major contribution from advances
in critical care to improved survival without transplantation and, secondly, the efcacy of liver
transplantation has never been established in either a randomised controlled trial or even a carefully
constructed case comparison study. The feasibility of liver transplantation in acute liver failure was
established in a series of patient series during the second half of the 1980s [118]. A call was made in
1990 for a controlled trial between specialist units.to establish the role of emergency hepatic
transplantation in patients with fulminant hepatic failure but this fell on deaf ears [19]. The arguments
proffered in support of a trial were generically sound but were overcome by counter-arguments that
careful selection of patients with the worst prognosis would deliver survival benet well beyond that
which need to be demonstrated in a randomised control trial. Subsequently, liver transplantation
became a standard treatment for patients with acute liver failure and accounts for 611% of transplant
activity in Europe and the US.
Liver transplantation should be viewed as an integral part of the management plan, complementing
the sophisticated critical care protocols that have been developed and have contributed signicantly to
the overall improved outcomes both with and without transplantation. Candidates for liver trans-
plantation should be identied soon after presentation, to maximise the time available to nd
* Fax: 44 207 346 3167.
E-mail address: john.ogrady@kcl.ac.uk.
Contents lists available at SciVerse ScienceDirect
Best Practice & Research Clinical
Gastroenterology
1521-6918/$ see front matter 2012 Published by Elsevier Ltd.
doi:10.1016/j.bpg.2012.01.012
Best Practice & Research Clinical Gastroenterology 26 (2012) 2733
a suitable organ, and with the highest attainable levels of certainty that each individual patient would
benet from the transplant. Achieving this end-point demands the high levels of specicity and
sensitivity fromthe selection process and current practice falls short of this aspiration. This has created
a tension in the selection process in that failure to list a patient for liver transplantation who subse-
quently dies is a visible and regrettable event, but transplanting a patient who would likely have
survived is a much less visible but equally regrettable outcome.
Prognosis is very variable in acute liver failure and an understanding of the issues that determine
prognosis is essential for the appropriate delivery of liver transplantation to this patient population.
Analysis of different cohorts has identied survival rates that can be as stark as 10% versus 90%. One
example is disease aetiology with outcome being much better for patients with acute liver failure
associated with paracetamol, pregnancy or hepatitis A (>5090%) than with seronegative hepatitis,
idiosyncratic drug reactions or Wilsons disease (<1020%), Other examples are the age of the patient
with outcomes best in those under the age of 3040 years, and the pace at which the disease progresses
with outcomes best in those with hyperacute liver failure.
Listing for liver transplantation
The principles driving selection processes are the accurate identication of those in need, as well as
those who will benet from, liver transplantation. Broadly, there are two approaches to listing patients
with acute liver failure for liver transplantation. The rst is to use some set of indicators of a poor
prognosis without liver transplantation, and the second is to list all patients with encephalopathy and
make the decision at the time a donor organ becomes available. Many clinical and investigational
parameters have been shown to reect prognosis in acute liver failure, but only about 10 are utilised in
the different approaches to identifying patients with a poor prognosis (Table 1).
Prognostic models
Prognostic models are widely used but the way they are perceived is strongly inuenced by whether
positive or negative predictive accuracy is deemed to be the most important function of any model.
A preference for positive predictive accuracy favours the individual patient and strives that all patients
who need a transplant get a transplant. This is an understandable clinical response but the down-side
of this approach is that the error rate translates to unnecessary transplants. Preference for negative
predictive accuracy minimises unnecessary transplants and ensures that an excessive proportion of
a limited resource is not diverted to the management of patients with acute liver failure. However, the
error rate with this approach translates to missed opportunities and avoidable deaths.
The Kings College criteria were described in 1989 and were the rst to differentiate between
paracetamol-induced and other aetiologies of acute liver failure [20]. The parameters tested were basic
clinical and laboratory data with the result that the resulting models were considered to be simple to
use and widely applicable. The non-paracetamol criteria are still used in the UK as originally described.
Table 1
Laboratory tests with prognostic value in acute liver failure.
Widely utilised
Coagulation parameters
Serum bilirubin
Serum transaminases
Serum creatinine
Arterial pH
Serum lactate
Restricted utilisation
Alpha-fetoprotein
Ammonia
Arterial ketone body ratio
Galactose elimination
Gc globulin
Serum phosphate
J. OGrady / Best Practice & Research Clinical Gastroenterology 26 (2012) 2733 28
In the paracetamol patients there have been a number of modications reecting improved survival
with medical management. In the original analysis the discriminatory power of a metabolic acidosis
with an arterial pH < 7.30 on the second or subsequent day after a paracetamol overdose was very
strong (95% mortality), but the more liberal use of N-acetylcysteine and aggressive early re-hydration
has reduced the signicance of a transient acidosis in isolation from other prognostic indicators.
Attempts were also made to increase the sensitivity of the paracetamol criteria but invariably there was
an associated reduction in specicity. The Kings college criteria were not validated in a number of rare
aetiologies particularly pregnancy-related syndromes, Wilsons disease and Amanita phalloides
poisoning and specic criteria for these conditions have subsequently been published.
Two meta-analyses have been performed on the Kings College criteria. One involved 18 studies and
1105 patients and yielded an overall specicity of 82% and sensitivity of 68% [21]. Specicity increased
to 93% in patients with more advanced encephalopathy and to 88% when the criteria were applied
dynamically, as was originally intended. The reduced sensitivity was most apparent in paracetamol-
induced acute liver failure. The second meta-analysis involving 1960 patients in 14 studies yielded
a specicity of 95% and a sensitivity of 58% but again the sensitivity was considered to have been
reduced by non-dynamic application [22].
The Clichy criteria were also dened in the 1988s, initially for hepatitis B related disease but were
subsequently used in other aetiologies of acute liver failure [23]. These apply when grade II enceph-
alopathy develops and the prognosis is then determined by age-adjusted factor V levels. The common
ground between Clichy and Kings College criteria was the use of coagulation tests and the recognition
that the prognosis of acute liver failure was worse in older patients.
A number of other criteria have subsequently been described. A study from India identied
six parameters age >50 years, jaundice to encephalopathy time greater than seven days, grade 34
encephalopathy, cerebral oedema, prothrombintime >35seconds andserumcreatinine >1.5mg/dl with
any three of these factors indicating a poor prognosis [24]. This approach combines early indicators of
prognosis with specic later complications that conrm the anticipated poor outcome i.e. advanced
encephalopathy and cerebral oedema. It is likely that future prognostic models with become time
dependent and more specic to the different stages of the evolving disease.
Recently MELD scores, introduced and validated for use in prognostication in chronic liver disease,
were used in assessing prognosis in non-paracetamol-related acute liver failure. This utility of MELD in
this way is not surprising given that the three components of MELD (bilirubin, INR, serum creatinine)
gure strongly in other prognostic models. However, a disadvantage of relying on MELD as the prog-
nostic model of choice is that it does not capture the three very important clinical characteristics
impacting on the natural history of acute liver failure mentioned above. Patients with subacute liver
failure in particular are potentially disadvantaged by MELD because of the less severe derangements of
coagulation tests and late occurrence of renal dysfunction. Only one of three studies found that MELD
outperformed the Kings College criteria in selecting patients for transplantation [2527]. It has been
suggested that MELD might be developed on an aetiology specic basis, and this is worthy of further
consideration, as is age modied MELDscores. A recently described variation of the MELDtheme was to
replace bilirubin with a marker of cell injury (cytokeratin 18) which yielded peak sensitivity and spec-
icity indices of 81% and 82%, respectively, in a series of patients of 68 patients of mixed aetiologies [28].
There are a number of disease specic prognostic models. Serum lactate levels in isolation were
found to predict survival in paracetamol-related. The original observation suggested a serum lactate
greater than 3.0 after uid resuscitation predicted a poor outcome [29]. However, this was not
conrmed in two subsequent studies and meta-analysis did not conrm the expectation that serum
lactate levels would complement the Kings College criteria [21,22,30,31]. Following Amanita phalloides
ingestion, the development of diarrhoea with eight hours was associated with 78% mortality and after
four days an INR greater than six had 100% mortality [32]. Alternatively, a prothrombin time less than
25% combined with a serum creatinine greater than 106 mmol/l were highly predictive of death [33].
Following hepatitis A, a combination of two laboratory parameters (ALT <2600 and creatinine
>2.0 mg/dl) and two clinical events (intubation and need for pressors) were identied as indicating
a poor prognosis [34]. A recent series of patients with pregnancy-related acute liver failure reported
a transplant-free survival of 80% and a serum lactate on admission of greater than 2.8 predicted death
with a sensitivity of 73% and a specicity of 75% [35].
J. OGrady / Best Practice & Research Clinical Gastroenterology 26 (2012) 2733 29
Radiology and histology
Assessment of the volume of viable hepatocytes by histologic examination is considered by some
to be of prognostic value. The critical mass that suggests a good prognosis has been calculated at
between 25 and 40%. This parameter has been used in isolation and in combination with other
criteria to select patients for liver transplantation, but the potential for sampling error is considerable.
A biopsy taken from an area of total collapse will show few viable hepatocytes even though the
adjacent tissue may be regenerating. In addition, the poor prognosis in patients with subacute liver
failure may not be apparent from the relative healthy appearance of a biopsy taken from a regener-
ative nodule.
A small liver on clinical or radiological assessment, or more particularly a liver that is found to be
shrinking rapidly, is a poor prognostic indicator. This feature is especially useful in subacute liver failure
when the degree of encephalopathy and the severity of the derangement of coagulation may not be
particularly marked. In Japan, CT scanning has been used to assess both the size of the liver and the
functional reserve and this was useful in determining prognosis. One such study described 77%
sensitivity and 92% specicity when CT-derived liver volumes were combined with serum bilirubin
levels [36]. Serial ultrasonic assessments of liver size are commonly used to detect changes in liver size,
but the ease with which this can be done has to be weighted against the relatively subjective
assessment of liver volume with this technique.
Clinical features
The severity of the clinical illness clearly has a signicant impact on survival. In particular, the grade
of encephalopathy correlates strongly with outcome, both in terms of the grade of encephalopathy at
the time of presentation to a specialist unit and the maximumgrade attained. Prognosis worsens when
grade 4 encephalopathy is complicated by cerebral oedema, and even further when the latter co-exists
with renal failure [37]. Nevertheless, some patients with these complications in the setting of hyper-
acute liver failure will recover without transplantation. In addition, subsets of patients have very poor
prognoses despite the absence of cerebral oedema or renal failure, particularly within the cohort with
subacute liver failure. These apparent paradoxes render reliance on clinical complications in isolation
problematic when assessing prognosis.
Grafts and graft allocation
Donor organ allocation systems usually prioritise patients with acute liver failure. Series from
specialised centres in the US, continental Europe and the UK are consistent in showing that 4551% of
patients admitted with acute liver failure underwent liver transplantation. The UK gures exclude
cases due to paracetamol and only 79% of these underwent transplantation. The waiting times for
donor organs are pivotal in determining the policy to liver transplantation and the US and UK allo-
cation systems now result in the majority of patients being transplanted within 48 hours of
registration.
Waiting times also inuence policy on the use of ABO mismatched grafts, steatotic livers, liver from
non-heart-beating deceased-donors and other suboptimal potential grafts. European registry data
show that the graft survival rate for ABO incompatible liver grafts used for emergency transplantation
was only 32% at one year, compared with 54% and 49% for matched and unmatched but compatible
grafts, respectively. Living-related donation is well established in Asia where deceased-donor donation
is limited, and is being increasingly used in Western countries.
Auxiliary liver transplantation
Auxiliary orthotopic transplantation has as a bridge to survival without the need for life-long
immunosuppression is an exciting concept. With this approach the right lobe is usually replaced but
the native left lobe remains in situ. In carefully selected series the native liver regenerates within 13
years to the degree that immunosuppression can be withdrawn slowly resulting in atrophy of the graft.
J. OGrady / Best Practice & Research Clinical Gastroenterology 26 (2012) 2733 30
The precise indications have not yet been determined but are inuenced the ability of the native liver to
regenerate to normal morphology with time as well as the absence of a clinical need for the immediate
benets of total removal of the diseased liver. Thus, paracetamol-induced liver failure and the
hyperacute syndromes are much more favourable candidates for this approach than patients with
seronegative hepatitis and the subacute syndromes. In the latter groups, regeneration may occur but
with signicant brosis or cirrhosis. Wilsons disease, autoimmune hepatitis and Budd-Chiari
syndrome are causes of acute liver failure that are not suitable for auxiliary transplantation. Severe
neurological and cardiovascular complications are stabilised by hepatectomy and patients with high
inotrope requirements or unstable cerebral oedema at the time of transplantation are unsuitable for
auxiliary liver transplantation.
In one study of 44 patients receiving auxiliary grafts, the survival rate at 30 months was 77% and 32%
of survivors had been completely weaned from immunosuppression at a median of 19 months with
other undergoing progressive reduction in immunosuppression [38]. Another study of 16 patients
reported a 5-year survival rate of 59% and 60% of survivors were totally weaned from immunosup-
pression [39]. However, one comparative study of 12 patients undergoing auxiliary liver trans-
plantation and 24 patients receiving conventional transplants found similar survival rates but higher
complication rates with auxiliary transplant (cerebral oedema and bacteraemia) and only 17% were
withdrawn from immunosuppression [40].
Post-operative management
Patients undergoing liver transplantation for acute liver failure have longer stays in intensive care
environments. Some of the clinical challenges in the management of acute liver failure are carried over
into this phase of the post-transplant course. Cerebral oedema is a case in point and monitoring of
intracerebral pressure and cerebral perfusion pressure should continue for 48 hours after trans-
plantation, or longer if graft functionis suboptimal. Infectionis another exampleandantimicrobial agents
are usually given for longer periods as compared with elective transplants. These patients are also often
considered amongst high-risk groups for fungal infection and receive prophylactic systemic antifungal
therapy. These patients are also more likely to have renal dysfunction and a need for renal support.
Immunosuppression strategies tend to reect the higher risk of rejection seen in the younger
patient population which is a feature of this population of liver transplant recipients. Recurrence of
hepatitis B is a risk, particularly in patients who were not HBV DNA negative at the time of trans-
plantation, and consequently most centres adopt immunoprophylaxis regimens as used in patients
with chronic hepatitis B infection. In theory a subgroup with de novo hepatitis B infection will have
cleared the virus by the time of transplantation and should not require immunoprophylaxis long-term.
These are recognisable by stable anti-HbsAg antibody levels as the interval between hepatitis B
immunoglobulins levels are gradually extended (usually under cover with an antiviral drug e.g. lam-
ivudine or tenofovir).
Results
The overall survival rates following transplantation were 63% in the US and 61% in Europe, and most
individual centres that have reported their experience had survival rates falling within the 5979%
range. An exceptional report of a 93% survival rate fromone centre in the US suggests that better results
are likely to be more routinely attainable [18]. Patients receiving liver transplants for acute liver failure
(median age 28 years) are younger those undergoing elective transplantation (median age 44 years).
Survival rates decrease with age as illustrated by European data indicating that the one and ve-year
survival rates are 51% and 42%, respectively, for patients aged 60 years or over. These gures compare
with survival rates of 61% and 55% at the one and ve years for the overall population of patients
receiving liver transplants for acute liver failure.
The factors that inuence outcome after liver transplantation are multiple. The aetiology of the
underlying disease correlated with outcome in some centres. The best results were achieved for
transplantation for Wilsons disease and the worst for idiosyncratic drug reactions. Patients who
survived liver transplantation for paracetamol-induced liver failure received the graft around the
J. OGrady / Best Practice & Research Clinical Gastroenterology 26 (2012) 2733 31
fourth day after drug ingestion, as compared with the sixth day in those who succumbed [3]. In that
study, no patient transplanted on or after the seventh day survived. This may reect the role of sepsis in
propagating the continued deterioration in these patients and the inability of liver transplantation to
positively inuence this complication.
Renal function correlates with outcome and one discriminatory serum creatinine level was as low as
1.45 mg [41]. Acidosis and Apache III score at the time of transplantation were good indicators of the
severity of the patients illness and correlated with outcome. However, none of these parameters were
sufciently discriminatory to use as criteria to disqualifying individual cases fromtransplantation. A risk
stratication has been proposed following an analysis of 1,457 patients who underwent liver trans-
plantationfor acuteliver failureintheUS[42]. Thefour factors identiedwereaBMI >30, serumcreatinine
>2 mg/dl, recipient age > 50 years and a history of life-support. The 5-year survival rate was 81% in the
low-risk patients as compared with 42% in the high-risk group. In seronegative hepatitis, high body mass
index, age over 50 and non-caucasian ethnicity were linked to early death after liver transplantation [43].
Conict of interest
None.
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Practice points
Recognise the condition based on short history, encephalopathy and coagulopathy
Understand the different patterns of disease
Implement aetiology specic therapies when these exist
Assess and update prognosis based on a recognised prognostic model
Consider need and suitability for transplantation as soon as feasible
Re-evaluate suitability for transplantation when an organ becomes available
Research agenda
Find new ways of assessing prognosis that deliver high levels of specicity as well as
sensitivity
Continue to develop liver support devices as bridges to liver transplantation
Understand the factors that cause the differential in survival in patients having emergency
and elective transplants
Continue to expand the use of auxiliary transplantation
J. OGrady / Best Practice & Research Clinical Gastroenterology 26 (2012) 2733 32
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