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LIVER TRANSPLANTATION 13:1389-1395, 2007

ORIGINAL ARTICLE

Acute Liver Failure in Spain: Analysis of 267

Cases
Àngels Escorsell,1,2 Antoni Mas,1,2 Manuel de la Mata,3 and the Spanish Group for the Study of Acute
Liver Failure*
1
Liver Unit, Institut Clinic de Malalties Digestives i Metabòliques, Hospital Clı́nic, and 2Institut d’Investigaciò
Biomedica August Pi i Sunyer, University of Barcelona, Catalonia; and 3Liver Transplant Unit, Hospital Reina
Sofı́a, Córdoba, Spain

The cause of acute liver failure (ALF) is a major determinant of its outcome. Acetaminophen (paracetamol) overdose is a
leading cause of ALF in some developed countries, whereas in others, such as Spain, it is extremely rare. To analyze the
etiology, characteristics, and outcome of ALF in Spain, we performed a retrospective analysis of 267 patients whom we
observed from 1992 to 2000. Seventeen tertiary-care hospitals with active liver transplantation (LT) programs contributed data.
Causes of ALF were viral hepatitis in 98 (37%; hepatitis B virus in 75 patients), unknown in 86 (32%), drug or toxic reactions
in 52 (19.5%; acetaminophen overdose in 6), and miscellaneous in 31 (11.6%). Overall survival was 58%. LT was performed
in 150 patients, with a survival of 69%. Despite fulfilling criteria, 51 patients were not transplanted because of contraindications;
their survival was only 7.8%. Forty-seven (85.5%) of 55 patients without transplant criteria survived. Hepatitis B virus is the
most common cause of ALF in Spain, although the origin of 30% of cases remains undetermined. Acetaminophen overdose
represents a very rare cause of ALF. LT was performed in ⬎50% of cases. Patients without transplant criteria had a very good
prognosis; those who fulfilled these criteria but who had contraindications for transplantation had a high mortality rate. Liver
Transpl 13:1389-1395, 2007. © 2007 AASLD.

Received July 28, 2006; accepted January 2, 2007.

from one area to another difficult.2 In fact, most studies

See Editorial on Page 1362
Acute liver failure (ALF) is a syndrome characterized by
the development of hepatic encephalopathy (HE) to-
gether with signs of hepatocellular insufficiency, espe-
cially jaundice and coagulation disorders, in patients
without previous liver disease.1 The prognosis of this
serious disorder improved dramatically with the intro-
duction of orthotopic liver transplantation (OLT) in the
late 1980s.
Epidemiological studies have pointed out that ALF is
a wide, heterogeneous syndrome involving several dis-
eases with different patterns, prognoses, and out-
comes. Furthermore, marked geographical differences
have been identified, making the translation of data
are from the United States (one of the studies involving
the whole country)3-6 and the United Kingdom (studies
from single centers),7,8 where acetaminophen (para-
cetamol) overdose accounts for 20-75% of all ALF
cases.3-8 There is general agreement that these figures
are markedly reduced in countries, such as Spain, in
which attempts at suicide by acetaminophen are anec-
dotal, a result of ignorance and the fact that acetamin-
ophen is not available over the counter.9-11 This differ-
ence, as well as its effect on the outcome of ALF (far
better in ALF due to acetaminophen ingestion3,4,12 and
hepatitis A3,4,13 than in ALF due to other causes) in
countries other than the United States, the United
Kingdom, and eastern countries, has been poorly inves-
tigated.

Abbreviations: ALF, acute liver failure; LT, liver transplantation; HE, hepatic encephalopathy; OLT, orthotopic liver transplantation;
HBV, hepatitis B virus.
Supported in part by a grant from Instituto de Salud Carlos III (RNIHG-C03/02).
* Members of the Spanish Group for the Study of Acute Liver Failure are listed at the end of the article.
Address reprint requests to Àngels Escorsell, MD, Liver Unit, IMD, Hospital Clı́nic, Villarroel, 170, 08036 Barcelona, Spain. Telephone: 34
932275499; FAX: 34 932279348; E-mail: aescor@clinic.ub.es
DOI 10.1002/lt.21119
Published online in Wiley InterScience (www.interscience.wiley.com).

© 2007 American Association for the Study of Liver Diseases.


1390 ESCORSELL ET AL.
The aim of the present study was to investigate the
clinical characteristics (including epidemiology and
etiology) and outcome of what is to date the most
extensive series of patients with ALF ever studied in
Spain.
PATIENTS AND METHODS
A questionnaire was given to hepatologists in 27 hospi-
tals around Spain to ascertain how many patients with
ALF were recorded from January 1, 1992, to December
31, 2000. All the centers involved had liver units and
were either referral centers for liver patients or liver
transplantation (LT) centers with at least 2 years’ expe-
rience in OLT. One doctor from each liver unit collected
all the cases handled in the unit during the period of
study. Each case was identified with the patient’s
name, date of birth, and hospital ID to avoid duplica-
tion. Diagnosis of ALF was established according to
clinical, analytical, and histological criteria, if available.
ALF was identified in the first health care center follow-
ing the accepted criteria: acute, life-threatening deteri-
oration of liver function in the absence of preexisting
liver disease characterized by the presence of jaundice,
impairment in liver function determined by the pro-
thrombin time (prothrombin index ⬍40% or interna-
tional normalized ratio of prothrombin time ⱖ1.5), and
encephalopathy, which can be a late symptom. In all
cases, data from all patients fulfilling these criteria were
collected, regardless of age, suspected cause of ALF, or
comorbidities. ALF was classified as fulminant when
HE appeared within the first 2 weeks after the onset of
jaundice and as subfulminant when appearing between
weeks 3 and 8.14 In addition, patients were also classi-
fied according to the O’Grady classification15 as having
hyperacute, acute, or subacute impairment.
We requested information for all patients admitted at
each center who met this definition. The following vari-
ables were recorded: demographic, clinical, laboratory,
and outcome data including LT, death, and survival
without OLT within the current admission. Etiologic
diagnoses were made at each study center on the basis
of accepted diagnostic criteria including clinical his-
tory, laboratory values, imaging studies, and, in some
cases, histologic characteristics. ALF was considered to
be indeterminate when clinical, laboratory evaluations
(including toxicological screening, serologic markers for
viral hepatitis A, B, and C, and autoantibodies), and
imaging studies were inconclusive.
The management of the whole series of patients, al-
though determined at each site, was uniform and fol-
lowed accepted published guidelines. In summary, it
includes prevention of hypoglycemia, bacterial and fun-
gal infections, upper gastrointestinal tract bleeding,
and renal failure; conventional treatment of HE and
hypovolemia or hypervolemia; monitoring of hemody-
namic (central venous or Swan-Ganz catheter) and oxy-
gen status (SaO2); and monitoring of the intracranial
pressure and electroencephalogram waveforms in pa-
tients presenting grade III or IV HE, and treating those
patients with pathological findings.
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All patients, especially those fulfilling criteria for LT,
were transferred to a LT unit. Candidacy for LT was
determined at each individual center according to the
King’s College Guidelines16 except for one center, which
used the following criteria to define the need for LT:
grade III or IV of HE regardless of the patient’s clinical
evolution; progression of encephalopathy after a tran-
sient period of improvement; and absence of improve-
ment after a 3-day period of supportive management in
patients with subfulminant ALF and grade I or II HE.17
Spontaneous survival was defined as survival with-
out OLT.
The questionnaires were checked for missing values
and inconsistencies at the data coordination center. To
assess the annual incidence and the point prevalence of
ALF in Spain, each participating center was asked to
provide the date of diagnosis of each patient as well as
the overall population it served.
Statistical Analysis
Data were entered into an Access database and ana-
lyzed by SPSS software (SPSS, Chicago, IL). Data are
reported as means with standard deviations. Categori-
cal variables were compared by the Fisher exact test,
and continuous variables were compared with the un-
paired Student t test (or nonparametric Mann-Whitney
rank sum test for unpaired data). The actuarial proba-
bility curves were constructed by the Kaplan-Meier
method and compared with the log rank test. Statistical
significance was established at a P value of ⬍0.05.
RESULTS
Seventeen centers from 11 autonomous communities,
covering a population of 21.66 million inhabitants, an-
swered the questionnaire. The total Spanish population
on January 1, 2001, was 41.11 million inhabitants. A
total of 267 patients with ALF were identified during the
9-year period. We are aware that the retrospective de-
sign of our study could be an important pitfall when
calculating the incidence of the disease. In fact, we
know that we lost patients from the 10 centers because
they did not give us their data, and we probably lost
data from other hospitals when they failed to refer their
patients to LT centers, mostly because the patients had
severe comorbidities that conferred a poor prognosis.
Taking into account these limitations, the estimated
incidence of ALF during the study period was of 1.4
cases per million inhabitants per year.
Demographic Characteristics and Clinical
Data
Age at diagnosis varied widely, from 1 to 79 years
(mean, 36.8 years), with 57% of patients younger than
40 at presentation. Twenty patients were children (ⱕ14
years). One hundred eighteen patients (44%) were male.
All patients but 7 (2.7%) were Spanish (although all
except one were white).
Fulminant hepatic failure accounted for 60% of
cases; 37% were subfulminant. According to O’Grady’s
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ACUTE LIVER FAILURE IN SPAIN 1391

classification, 42% were hyperacute, 38% acute, and

16% subacute. Time from jaundice to encephalopathy
could not be accurately established in 9 cases.
At presentation, grade I HE was the most frequent
finding (48%), with only 13% of the patients presenting
deep coma (grade IV HE), although these figures re-
versed during follow-up (40% of the patients developed
grade IV, whereas 16% remained in grade I). The mean
interval from onset of symptoms to encephalopathy was
15.8 ⫾ 17 days.
It is of note that 15 patients (5.6%) had no HE at
presentation but developed it during admission.

Causes of ALF Figure 1. Outcome of 267 patients with acute liver failure.
Viral hepatitis was the most frequent cause of ALF,
accounting for 98 patients (37%). Among these 98 pa-
or IV HE). Cerebral edema, diagnosed either by intra-
tients, 75 (28%) had acute hepatitis B, 11 (4%) had
cranial pressure monitoring or by combined clinical
hepatitis B and D, and acute hepatitis A and C ac-
and computed tomography data, was found in 88 pa-
counted for 5 (2%) patients each. Two patients had
tients (33.7%).
nonhepatotrophic viruses causing ALF.
Cryptogenic/indeterminate liver failure was the sec-
ond most common cause of ALF involving 86 patients Outcome
(32.2%).
The overall survival was 155 (58%) of 267 patients (Fig.
Drug or toxic reactions were responsible for 52 cases
1). Two hundred twelve fulfilled criteria for emergency
(19.5%) of ALF. Acetaminophen was the less commonly
OLT, with 150 receiving a liver graft (56% of the overall
implicated drug, being responsible for only 6 cases
series, 71% of those patients fulfilling criteria for trans-
(2.2%). Idiosyncratic reactions to antituberculosis ther-
plantation). The survival among this group of trans-
apy were deemed responsible for 13 cases (4.9%), and
planted patients was 69.3% (104 patients). Eleven pa-
Amanita mushroom poisoning was responsible for 10
tients died while waiting for a graft (4% of the overall
cases (3.7%). The remaining 23 cases were due to dif-
series), and the remaining 51 patients (19.1%) were not
ferent toxic substances or drugs.
transplanted because of contraindications to the pro-
Last, there was a miscellaneous group of 31 patients
cedure. These contraindications were: advanced age
(11.6%), including 13 cases (4.9%) of autoimmune hep-
(⬎65 years, 18 cases), expected short-term survival due
atitis, presenting as ALF; 6 cases (2.2%) of ischemic
to concomitant diseases (acquired immunodeficiency
origin; 8 cases (3%) of a neoplastic infiltration; 2 cases
syndrome in 4 cases, disseminated cancer in 10 cases),
(0.7%) of acute Wilson disease; and 2 cases (0.7%) of
severe active systemic bacterial infections precluding
acute fatty liver of pregnancy.
OLT (5 cases), other organ failure (3 cases), or active,
There were significant differences in the cause of ALF
repeated, and long-term drug addiction (11 cases, 22%
according to the period of study (P ⫽ 0.003). From 1992
of the group of patients in whom OLT was contraindi-
to 1995, 61 (42%) of 145 cases were due to viral infec-
cated). Four patients in this group survived (Fig. 1).
tion; this percentage fell to 37 (30%) of 122 cases in the
Fifty-five patients were considered to not fulfill crite-
next 5 years. Conversely, there was an increase in the
ria for emergency OLT (Fig. 1). Eight patients of this
incidence of toxic substance– or drug-related ALF dur-
group (14.5%) finally died from nonhepatic causes; the
ing the last period of the study (27% vs. 13% in the
remaining 47 patients survived (85.5% of the group)
former).
(Table 1).

Extrahepatic Complications Emergency OLT Status Comparison

Sixty-two percent of the patients presented medical
complications at admission. The most frequent compli-
cation was the development of hypoglycemia (26%) fol-
lowed by ascites (24%), upper gastrointestinal bleeding
(15%), clinical signs of cerebral edema (14.7%), respi-
ratory failure (10%), and overt infection (9%).
During follow-up, the incidence of these complica-
tions increased to up to 75% of the patients. Forty-three
patients (16%) had intracranial pressure monitoring by
an extradural device placed as per protocol (clinical
suspicion of cerebral edema or progression to grade III
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
According to the presence or absence of criteria to per-
form emergency OLT, patients could be classified as
those fulfilling OLT criteria and entering the waiting list
(group 1), those not fulfilling OLT criteria (group 2), or
those who, despite reaching OLT criteria, could not be
transplanted because of contraindications to the pro-
cedure (group 3). Group 1 included 150 patients who
received liver grafts (Table 2), and 11 died while waiting
for a liver.
In the group of transplanted patients, the median
time from listing to actual OLT was 39 ⫾ 39 hours.
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1392 ESCORSELL ET AL.

TABLE 1. Baseline and Follow-up Characteristics of Patients in the Study According to Emergency OLT Status

Group 2 (no Group 3 (OLT

Group 1* (OLT OLT criteria) contraindicated)
Variable criteria) (n ⫽ 161) (n ⫽ 55) (n ⫽ 51) P
Age (yr), median (range) 33 (1-69) 31 (1-78) 54 (2-79) 0.0001
Gender (M/F) 60/101 27/28 31/20 0.009
Days of jaundice-HE, median (range) 13 (1-120) 7 (1-48) 7 (1-39) 0.0001
HE at admission (%) 0.015
0 11% 0% 4%
I 34% 59% 35%
II 27% 17% 31%
III 17% 17% 14%
IV 11% 7% 16%
Hospitalization (days), median (range) 28 (1-330) 13 (1-380) 7 (1-47) 0.0001
Etiology, n (%) 0.012
Virus 59 (36.7%) 22 (40%) 17 (33.3%)
Toxic 24 (14.9%) 13 (23.6%) 15 (29.4%)
Unknown 63 (39.1%) 9 (16.4%) 14 (27.5%)
Other 15 (9.3%) 11 (20%) 5 (9.8%)
Viral ALF, n (% of all series) NS
HBV 44 (27.3%) 15 (27.2%) 16 (31.4%)
HBV⫹HDV 7 (4.3%) 4 (7.3%) 0
HAV 3 (1.9%) 2 (3.6%) 0
HCV 5 (3.1%) 0 0
Other viruses 0 1 (1.8%) 1 (2%)
Complications during admission, n (%)
Hypoglycemia 38 (24.4%) 14 (26.4%) 23 (46.9%) 0.009
Bleeding 18 (11.5%) 7 (13%) 16 (32.7%) 0.002
CRRT needed 12 (7.7%) 4 (7.4%) 6 (12%) NS
Respiratory failure 23 (14.6%) 7 (13%) 17 (34.7%) 0.003
Severe infections 29 (18.7%) 17 (31.7%) 28 (56%) 0.0001
Cerebral edema 64 (40.5%) 6 (11.1%) 18 (36.7%) 0.0001
Shock 11 (7.2%) 4 (7.5%) 21 (42.9%) 0.0001
Coma (grade IV HE) 10 (18.9%) 60 (37.3%) 37 (74%) 0.0001
Outcome (end of hospitalization), n (%) 0.0001
Alive 104 (64.6%) 47 (85.5%) 4 (7.8%)
Dead 57 (35.4%) 8 (14.5%) 47 (92.2%)

Abbreviations: OLT, orthotopic liver transplantation; HE, hepatic encephalopathy; ALF, acute liver failure; HBV, hepatitis B
virus; HDV, hepatitis D virus; HAV, hepatitis A virus; HCV, hepatitis C virus; CRRT, continuous renal replacement therapy.
*Group 1 included those patients listed for emergency OLT but who died while waiting for a graft.

Eighty-three patients underwent OLT 24 hours or less
after inclusion on the waiting list (51.5% of the 161
patients listed for emergency OLT, 11 of whom died
before receiving the graft). The mean age of the trans-
planted patients was 34 ⫾ 17 years, and 63% were
women. The main cause was unknown (in 39% of the
cases) followed by hepatitis B virus (HBV)-related ALF
(27%). HE was predominantly mild (grade I) at admis-
sion, although it changed to grade II to IV during fol-
low-up with no differences compared with the overall
series of patients. As expected, these transplanted pa-
tients experienced fewer complications during fol-
low-up than those not receiving OLT despite its being
indicated (Tables 1 and 2).
The patients not receiving a liver graft because of
contraindications to OLT were predominantly men
(60%) with a mean age of 48 ⫾ 21 years. The main cause
of ALF in this group was HBV (Table 1). The incidence of
complications, both at admission and during follow-up,
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
was higher in this group compared with the overall
series and the patients receiving OLT. Liver function
tests and other analytical parameters were similar in
the 2 groups (data not shown).
Patients who did not fulfill criteria for LT were equally
distributed by gender (1:1), with a mean age of 34 ⫾ 16
years. As in the other groups, the main cause was
HBV-related ALF. Complications were less frequently
observed both at admission and during follow-up (Table
1). Prothrombin time remained lower compared with
the other 2 groups of patients throughout hospitaliza-
tion (25.9 ⫾ 19% vs. 16.6 ⫾ 10.8% in patients of group
1 vs. 14.9 ⫾ 9.9% in patients of group 3; P ⬍ 0.0001).
There were no statistically significant differences in
other analytical parameters (data not shown).
When we excluded data from patients from the cen-
ter without the use of the King’s College Criteria to
define the need for emergency LT, the results did not
differ.
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ACUTE LIVER FAILURE IN SPAIN 1393

TABLE 2. Characteristics of the Patients Fulfilling Criteria for Emergency OLT According to Final Evolution*

Variable OLT (n ⫽ 150) No OLT (n ⫽ 62) P

Age (yr), median (range) 32 (1-69) 50 (2-79) 0.0001
Gender (M/F) 55/95 36/26 0.004
Days of jaundice-HE, median (range) 14 (1-120) 7 (1-56) 0.003
HE at admission (%) NS
0 12% 3%
I 33% 37%
II 28% 27%
III 16% 18%
IV 11% 14%
Hospitalization (days), median (range) 30 (2-330) 6 (1-47) 0.0001
Etiology, n (%) NS
Virus 56 (37.3%) 20 (32.3%)
Toxic 21 (14%) 18 (29%)
Unknown 59 (39.3%) 18 (29%)
Other 14 (9.3%) 6 (9.7%)
Viral ALF, n (% of all series) NS
HBV 41 (27.3%) 19 (30.6%)
HBV⫹HDV 7 (4.7%) 0
HAV 3 (2%) 0
HCV 5 (3.3%) 0
Other viruses 0 1 (1.6%)
Complications during admission, n (%)
Hypoglycemia 35 (24.1%) 26 (43.3%) 0.006
Bleeding 14 (9.7%) 20 (33.3%) 0.0001
CRRT needed 8 (5.5%) 10 (16.4%) 0.012
Respiratory failure 18 (12.3%) 22 (36.7%) 0.0001
Severe infections 27 (18.8%) 30 (49.2%) 0.0001
Cerebral edema 56 (38.1%) 26 (43.3%) NS
Shock 7 (4.9%) 25 (42.4%) 0.0001
Coma (grade IV HE) 53 (35.3%) 44 (72.1%) 0.0001
Outcome (end of hospitalization), n (%) 0.0001
Alive 104 (69.3%) 4 (6.5%)
Dead 46 (30.7%) 58 (93.5%)

Abbreviations: OLT, orthotopic liver transplantation; HE, hepatic encephalopathy; ALF, acute liver failure; HBV, hepatitis B
virus; HDV, hepatitis D virus; HAV, hepatitis A virus; HCV, hepatitis C virus; CRRT, continuous renal replacement therapy.
*Patients actually transplanted (OLT) or not (no OLT, including patients with contraindications to OLT and those who died
while on the waiting list).

DISCUSSION result of psychiatric contraindications), and has a spe-

At present, large, published epidemiological studies on
ALF involving more than a single center (national sur-
veys) have only been performed with Anglo-Saxon pop-
ulations3-8 and in Eastern countries.9,11 The observed
discrepancies in the management and prognosis of ALF
patients may be the result of differences in etiologies
(i.e., acetaminophen in the United Kingdom and the
United States, and hepatitis E in India) and in the
capacity to perform emergency OLT. It is important to
emphasize that etiology may be a key factor determin-
ing the outcome of these patients, even in developed
countries with facilities for emergency OLT. Acetamin-
ophen overdose, either accidental or with suicidal in-
tent, is the major cause of ALF in the United Kingdom
(50-70%),7,8 and it accounts for a high proportion of
cases in the United States (19-39%).3-6 This etiology
clearly differs from others because it carries a better
prognosis,3,4,12 results in a lower likelihood of LT in
cases with indication for emergency OLT (mainly as a
LIVER TRANSPLANTATION.DOI 10.1002/lt. Published on behalf of the American Association for the Study of Liver Diseases
cific and effective treatment.12,18
The current study analyses the cause and outcome of
ALF in Spain. It should be stressed that the retrospec-
tive design of the study did not allow us to reach con-
clusive results, and we recommend careful interpreta-
tion until a prospective study can confirm the results.
Our data show an extraordinarily low incidence of
acetaminophen-related ALF, accounting for ⬍2.5% of
cases. These results clearly contrast with those ob-
served in Anglo-Saxon3-8 and other non–Anglo-Saxon
developed countries (France; J. Bernuau, personal
communication), which are seeing a progressive in-
crease of this etiology. The low incidence of acetamino-
phen overdose is probably because in Spain, it is rarely
used as a method of suicide, and because acetamino-
phen is not an over-the-counter drug, as it is in other
countries.
The main causes of ALF in Spain are HBV infection
and cryptogenic or indeterminate causes. Two-thirds of

1394 ESCORSELL ET AL.
our cases were due to these 2 causes. Toxic substances
or drugs other than acetaminophen, mainly antituber-
culosis drugs, were responsible for nearly 20% of the
cases. Because all these causes result in a worse prog-
nosis than acetaminophen overdose and infection with
hepatitis A or E, the global expected death rate in cases
not receiving emergency OLT in our series would have
been high. In a series from one of the participating
centers before the OLT era, the overall mortality was
78.4%.19 Thus, considering that all 212 patients who
fulfilled OLT criteria had a ⬎90% probability of dying
(93.5%, Table 2) if they did not undergo OLT, the ex-
pected mortality rate in our whole series of patients
would be 77.1%. This figure is in keeping with the
mortality reported in drug-induced ALF (75%) and ALF
of indeterminate origin (83%) if emergency OLT is not
performed, and it clearly contrasts with the spontane-
ous survival of acetaminophen-related ALF in recently
published series in the United States (68%).3
As shown in the Results, the incidence of viral ALF
decreased in the course of the study. This decrease
would tend to increase during the next few years as a
result of the introduction of HBV vaccination. HBV vac-
cine was introduced as universal and mandatory in
young adolescents in 1991, but it was not uniformly
performed throughout the country. Unfortunately, no
information regarding the profile of ALF in Spain after
universal HBV vaccination is available yet.
The prognosis of ALF has been dramatically changed
by the introduction of emergency OLT. In this sense, the
overall survival observed in our patients was 58% (35%
increase in survival from that expected without emer-
gency OLT). By using the classical King’s College crite-
ria for emergency OLT in all centers except one, which
applies another previously reported score,17 patients
who were not transplanted because they did not fulfill
these criteria had an excellent survival (85.5%, Table 1).
Moreover, death in this group of patients (8 cases) was
due to extrahepatic causes. There were no differences
in ALF etiology between patients who did or did not
fulfill the criteria for emergency OLT (Table 1).
It is important to note that despite having a very short
listing time (⬍24 hours in nearly half of the listed pa-
tients), 11 patients died while waiting for a graft. This
figure is nevertheless clearly lower than that observed
in United States, where ⬎30% of patients listed for
emergency OLT died while waiting for a graft.3 The dif-
ferences may be the result of the Spanish policy for
obtaining and distributing liver grafts. When one pa-
tient enters the waiting list because of ALF, a “0 alert” is
activated, and therefore, the first cadaveric liver avail-
able in the country goes to this patient, even if it is not
compatible (although we usually wait for a compatible
organ). By following this policy, the median time on the
waiting list for ALF patients (including primary liver
dysfunction after elective OLT) in 2005 was of 3.5 days
(range, 1-98 days), with 71% of the grafts ABO compat-
ible (National Transplant Organization, ONT, Liver
Transplantation Report 2005). However, the objective
should be no deaths on waiting list. That is why we
consider it to be extremely important to transfer pa-
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tients with severe acute hepatitis to transplant centers
as soon as possible for inclusion on the waiting list
immediately after identifying the need for emergency
OLT. Furthermore, it should be remembered that “the
liver fails before encephalopathy.”20 Consequently, 15
patients in our series (5.6%) showed no encephalopathy
at admission but developed it while hospitalized.
Fifty-one patients were not listed for emergency OLT
despite fulfilling the criteria because of contraindica-
tions to the procedure. Some of these contraindica-
tions, but not all, were unavoidable. Others, such as
active and severe infections, brain edema, and multior-
gan failure, were of note mainly because there are effi-
cient preventive and therapeutic maneuvers that now-
adays should be applied in all patients with ALF. The
need to know and apply these measures, as well as
others directed at specifically preventing liver damage,
means that we highly recommend the transfer of these
patients to LT units at diagnosis.
In summary, acute HBV infection is the most com-
mon cause of ALF in Spain, followed by drug or toxic
reactions. Among those, acetaminophen overdose
represents a very rare cause. It is of note that, despite
an exhaustive search for possible etiologies, ⬎30% of
cases remain of undetermined origin. LT was highly
applicable in those patients fulfilling emergency OLT
criteria (⬎70%) with a good survival rate. Patients who
did not reach transplant criteria had a very good prog-
nosis. On the other hand, patients with OLT criteria but
with contraindications for transplantation showed an
extremely poor prognosis.
These results should be considered cautiously be-
cause of the retrospective design and the need to the
findings to be confirmed by a prospective study. The
future study should focus on the possible changes in
both the etiology of ALF (the role of HBV after the intro-
duction of HBV vaccine as well as the drugs most com-
monly involved in ALF) and its outcome (e.g., applica-
bility and results of artificial liver support or albumin
dialysis, improvement of the criteria for emergency
OLT).
ACKNOWLEDGMENTS
The Spanish Group for the Study of Acute Liver Failure
includes: Hospital Clı́nic, Barcelona: J. Tost, J.M.
Salmeron, J. Fernàndez; Hospital Reina Sofı́a, Cór-
doba: J.L. Montero; Hospital Universitari La Fe, Valen-
cia: J. Berenguer; Hospital 12 de Octubre, Madrid: G.
Castellano; Arantzazu Ospitalea, Donostia: A. Castiella;
Hospital Puerta del Mar, Cádiz: F. Dı́az; Hospital Uni-
versitario Marqués de Valdecilla, Santander: E. Fáb-
rega; Clı́nica Universitaria, Pamplona: J.I. Herrero;
Hospital Infantil La Paz, Madrid: P. Jara; Hospital Vir-
gen de las Nieves, Granada: R. Martı́n-Vivaldi; Com-
plexo Hospitalario Juan Canalejo, A. Coruña: A. Otero;
Hospital Central de Asturias, Oviedo: L. Rodrigo; Hos-
pital, Vigo: D. Rodrı́guez; Hospital Gregorio Marañón,
Madrid: M. Romero Portales; Hospital Son Dureta, Ciu-
tat de Mallorca: P. Vaquer; Hospital Universitari Vall

d’Hebron, Barcelona: V. Vargas; Hospital Universitario
del Rı́o Hortega, Valladolid: R. Velicia.
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