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Mortality Analysis of Acute Liver Failure in Uruguay
Mortality Analysis of Acute Liver Failure in Uruguay V. Mainardia,b,*, K. Randoa,b, D. Olivaria,b, G. Reya, J. Castellib, G. Greccob, A. Leitesa,b, M. Harguindeguya,b, and S. Geronaa,b a Hepatic Biliary and Pancreatic National CenterdTeaching and Assistance Unit (UDA) from Uruguay University (UDELAR), Montevideo, Uruguay; and bNational Liver Transplant Program, Hospital Central de las Fuerzas Armadas, Montevideo, Uruguay
ABSTRACT Background. Acute liver failure (ALF) is a syndrome with high mortality. Objective. Describe characteristics and outcomes of patients with ALF in Uruguay, and identify factors associated with mortality. Methods. A retrospective analysis of 33 patients with ALF was performed between 2009 and 2017. Results. The patients’ median age was 43 years, and 64% were women. Average Model for End-Stage Liver Disease (MELD) score at admission was 33. The median referral time to the liver transplant (LT) center was 7 days. The most common etiologies were viral hepatitis (27%), indeterminate (21%), autoimmune (18%), and Wilson disease (15%). Overall mortality was 52% (71% of transplanted and 46% of nontransplanted patients). Dead patients had higher referral time (10 vs 4 days, P ¼ .008), higher MELD scores at admission (37 vs 28) and highest achieved MELD scores (42 vs 29; P < .001), and higher encephalopathy grade III to IV (94% vs 25%, P < .001) than survivors. Patients without LT criteria (n ¼ 4) had lower MELD score at admission (25 vs 34, P ¼ .001) and highest achieved MELD score (27 vs 37, P ¼ .008) compared with the others. Patients with LT criteria but contraindications (n ¼ 7) had higher MELD scores at admission (38 vs 31, P ¼ .02), highest achieved MELD scores (41 vs 34, P ¼ .03), and longer referral time (10 days) than those without contraindications (3.5 days) or those without LT criteria (7.5 days, P ¼ .02). Twenty-two patients were listed; LT was performed in 7, with a median time on waiting list of 6 days. Conclusions. ALF in Uruguay has high mortality associated with delayed referral to the LT center, MELD score, and encephalopathy. The long waiting times to transplantation might influence mortality.
A
CUTE LIVER FAILURE (ALF) is a syndrome characterized by the development of coagulopathy and encephalopathy in patients without previous liver disease [1]. The incidence is low: 2000 cases per year in the United States (estimated at 6.2 per million inhabitants per year) [2,3], 1 to 8 cases per million inhabitants per year in the United Kingdom [4,5], and 1.4 per million inhabitants per year in Spain [6]. ALF has a high mortality rate, although the prognosis has dramatically improved since the introduction of liver transplantation (LT) in the late 1980s along with advances in critical care. In the 1970s, the global mortality rate was 83% ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 465e471 (2018)
to 85% [7,8], and currently the rates are 38% in Europe [8] (42% in Spain [6]) and 33% in the United States [9]. There was a difference in the survival of patients who did not receive a transplant compared with those who did in Europe between 2004 and 2008 (48% and 86%, respectively)
*Address correspondence to Victoria Mainardi, MD, José Felix Zubillaga 1133/1, CP11300, Montevideo, Uruguay. Tel: þ598 99 59 74 86. E-mail: [email protected] or victoria_mainardi@ hotmail.com 0041-1345/18 https://doi.org/10.1016/j.transproceed.2017.12.037
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[8], as well as in the United States between 1998 and 2001 (43% and 84%, respectively) [9]. ALF accounted for 8% of indications for LT in Europe. Survival rates at 1, 3, and 5 years have improved over the past 20 years and are currently 79%, 75%, and 72%, respectively. However, survival is lower than that of elective transplant [10]. In the United States, ALF accounted for 3.3% of the indications for LT, and the survival rate at 1 year is above 80% [3,11]. The utilization of LT in ALF varies between different countries (18.2% in Europe [7], 29% in the United States [9], and 54% in Argentina [12]), transplant centers in the same country, and different etiologies [1]. In Europe the most common cause is drug-induced hepatotoxicity [8]; in United Kingdom, induced by Paracetamol [4], and in other areas such as Spain induced by non-Paracetamol drugs [6]. In the United States, Paracetamol hepatotoxicity is also the leading cause [9]. Viral hepatitis is the most frequent cause in South America [12], Asia [13,14], and Africa [15]. The following factors are recognized to contribute to a poor prognosis in ALF: advanced age, unfavorable etiologies (such as indeterminate, non-Paracetamol drug hepatotoxicity, and Wilson disease), subacute impairment, advanced encephalopathy, severe liver injury, extrahepatic failure (particularly renal failure), and late referral to a specialized unit [1,8,9,12,16,17]. The prognosis after listing for LT depends on the availability of a compatible donor organ, which depends on the number of available donors (donation rate and population) and the organ allocation system [18]. Mortality determinants after LT in ALF patients have been studied. Data from the European Liver Transplant Register identify the following determinants: recipient age >50 years and male sex, donor age >60 years, and incompatible ABO group [10]. The United Network for Organ Sharing cites the following determinants: recipient age >50 years, body mass index 30 kg/m2, creatinine >2 mg/dL, and history of life support [19]. King College Hospital identifies 4 variables: age of the recipient >45 years, requirement of vasopressors, and suboptimal donor defined by the presence of 2 of the following: age >60 years, steatosis, nonidentical ABO group, and reduced graft [20]. Other factors that have been shown to be associated with post-transplant mortality are elevated Model for End-Stage Liver Disease (MELD) scores [21] and a prolonged waiting list time [22]. Uruguay has a population of 3,440,000 (in 2014) [23] and has a single National Liver Transplant Program, which operates in the Military Hospital, and is an adult-only program. There is only one national waiting list; ALF has the highest priority, categorized as an emergency. Our objective is to describe the characteristics and outcomes of patients with ALF in Uruguay and identify the possible factors associated with mortality.
MAINARDI, RANDO, OLIVARI ET AL Program between April 2009 and April 2017 was performed. Approval from the Institutional Research Board was obtained. All enrolled patients met entry criteria for ALF: presence of coagulopathy (international normalized ratio 1.5) and any grade of hepatic encephalopathy (HE) within 26 weeks of the onset of symptoms, without underlying liver disease. Patients with Wilson disease, hepatitis B virus infection, or autoimmune hepatitis with cirrhosis were included if their disease had been recognized for <26 weeks [7]. Demographic, clinical, etiologic, laboratory, therapeutic, organizational data (referral time defined as the period between the first medical appointment and the contact with the LT program, waiting list time), and outcomes (mortality at discharge) were collected. The HE was graded from I to IV according to the West Heaven criteria [24]. ALF was classified as hyperacute, acute, or subacute impairment according to O’Grady classification [25]. Etiologic diagnoses were made based on accepted diagnostic criteria, including clinical history, laboratory values, imaging studies, and, in some cases, histologic characteristics. ALF was considered indeterminate when clinical, laboratory evaluation including toxicologic screening, serologic markers for viruses and antibodies, imaging studies, and histology (when available) were inconclusive. The management of the patients followed published guidelines. Medical treatment measures included prevention of hypoglycemia, bacterial and fungal infections, upper gastrointestinal tract bleeding and renal failure, treatment of HE, correction of blood volume and electrolyte and acid-base disorders, administration of coagulation factors if active bleeding or performing invasive procedures, and specific etiologic treatment if was available. Patients with HE grade II were given N-acetylcysteine. Extracorporeal hepatic support (Prometheus, Fresenius Medical Care, Germany) was performed in 2 patients. Candidacy for LT was determined according to the King’s College criteria (KCC) proposed by O’Grady et al [16]. The MELD score [26] was determined. The following contraindications for LT were defined: irreversible brain injury, unsolved active infection, multiple organ dysfunction with more than 3 organs compromised, extrahepatic cancer, and severe extrahepatic diseases that could not be solved with combined transplantation. In the patients who were transplanted, orthotopic LT of cadaveric donor was performed.
Statistical Analysis Numerical variables are expressed as means and standard deviations in case of normal variables and median and interquartile range (IQR) in case of non-normal variables. The statistical significance of differences between groups was calculated using a Student t test for independent samples in the case of normal variables and a Wilcoxon rank test in case of non-normal variables. c2 Test with Yates correction was used for categorical variables, which are expressed in percentages. The statistical software used was R (version 3.4.0; R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was tested with a 95% of confidence (exceptions were clarified on the text).
RESULTS METHODS Patients and Methods A retrospective analysis of 33 charts of adult patients (older than 14 years) hospitalized with ALF at the National Liver Transplant
Thirty-three patients were included. The estimated incidence of ALF during the study period was 1.2 cases per million inhabitants per year (this may be underestimated due to patients not being referred to the LT program).
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During this period 148 LTs were performed, with ALF accounting for 5% of the indications.
ALF N=33
Demographic and Clinical Characteristics
The median age was 43 years (IQR ¼ 27; minimum ¼ 17 and maximum ¼ 64), and 64% of the patients were women. According to O’Grady classification, 12 were hyperacute (36%), 14 were acute (42%), and 7 were subacute (21%). The mean MELD score at admission was 33 8, and the mean highest MELD score achieved was 36 9. Twenty patients (61 %) had HE grade III to IV. The median referral time was 7 days (IQR ¼ 12), with a minimum of 0 and maximum of 60 days. The median waiting list time was 7 days (IQR ¼ 12), with a minimum of 1 and maximum of 90 days. The most frequent cause of ALF was viral hepatitis (27%, hepatitis B in 8 cases and hepatitis A in 1 case). Indetermined ALF accounted for 7 cases (21%), autoimmune hepatitis 6 cases (18%), and Wilson disease 5 cases (15%). Hepatotoxicity accounted for 2 patients (6%): one for nonsteroidal antiinflammatory drugs and the other for Amanita phalloides poisoning. No paracetamol hepatotoxicity was reported. Budd-Chiari syndrome, ischemic hepatitis, heat shock, and graft-vs-host disease each accounted for 1 case (3%). Outcomes
Outcomes are depicted in Fig 1. Four patients did not meet KCC. Of the 29 patients who fulfilled criteria, 7 had contraindications for LT. Twenty-two patients were listed: in 7 cases (21% of the total ALF) LT was performed, 10 patients recovered without LT, and 5 died on waiting list. The overall mortality was 52% (17 patients). Mortality in the transplanted group of patients was 71% (5 of 7 patients) and in the nontransplanted group was 46% (12 of 26 patients; 7 patients had contraindications for LT and 5 died while waiting for a graft). The mortality of patients on the waiting list was 23%. The overall survival was 48% (16 patients). In 2 patients, LT was performed. Fourteen patients survived without LT, 4 never met KCC, and 10 met the criteria at admission but improved with medical treatment, so they were delisted.
n-KCC
w-KCC N=29
N=4 4 survived
w-KCC / w-CO N=7
w-KCC / n-CO N=22
7 died
LT – N = 7
5 died 2 survived R-list - N = 10
10 survived D-list – N = 5 5 died
Fig 1. Groups and outcomes of the 33 patients included in this study. ALF, acute liver failure; D-list, group of patients that died in waiting list; LT, group of transplanted patients; n-KCC, group without transplant criteria according to King College; R-list, group of patients that recovered spontaneously without liver transplantation and were retired from the list; w-KCC, group meeting transplantation criteria according to King College; w-KCC/n-CO, group meeting transplant criteria without contraindications; w-KCC/w-CO, group meeting transplantation criteria but with contraindications for transplantation.
did not meet emergency transplant criteria at admission or during the evolution. All survived (0% mortality). The median age was 35 (IQR ¼ 22). The mean MELD score at admission (25 3) and the highest achieved MELD score (27 5) were lower in this group of patients than in the remaining 29 cases (34 8 at admission, P ¼ .001; and 37 8 highest score, P ¼ .008). None of the patients presented HE grades III or IV. Only one had an unfavorable etiology,
Variables Associated With Mortality
Table 1 shows the variables associated with mortality. Patients who died (with or without LT) had significantly higher MELD scores at admission (mean 37 vs 28) and highest achieved (mean 42 vs 29; P < .001 in both cases) and a higher proportion of HE grades III to IV than the survivors (94% vs 25%, P < .001). The proportion of unfavorable etiologies and subacute impairment was higher among dead patients, but no significance could be demonstrated. Patients who died had a longer referral time than those who survived (median 10 vs 4 days, P ¼ .008).
Table 1. Factors Associated With Poor Prognosis of ALF in the Groups of Dead Patients Death (n ¼ 17)
Alive (n ¼ 16)
P Value*
43 16 (94%)
41 4 (25%)
.39 <.001
9 (53%) 5 (29%) 37 42 10
4 (25%) 2 (13%) 28 29 4
.20 .45 <.001 <.001 .008
Group Not Meeting Criteria for Transplantation
Median age (y) Encephalopathy grades III to IV, n (%) Unfavorable etiology, n (%) Subacute impairment, n (%) Mean MELD at admission Highest MELD achieved Median referral time (d)
The group not meeting criteria for transplantation (n-KCC) included 4 patients. Twelve percent of patients with ALF
Abbreviations: ALF, acute liver failure; MELD, Model for End-Stage Liver Disease. *In all cases the P values refer to a one-sided test.
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MAINARDI, RANDO, OLIVARI ET AL
and none had subacute impairment. Median referral time was 7.5 days (IQR ¼ 3), with a minimum of 0 and a maximum of 13 (Tables 2 and 3). Group Meeting Transplantation Criteria But With Contraindications
Seven patients comprised the group meeting transplantation criteria but with contraindications (w-KCC/w-CO). Twentyone percent of the patients fulfilled transplant criteria but had contraindications. These contraindications were related to ALF in 6 patients and in 1 patient was severe cardiovascular comorbidity. All died (100% mortality). This group contributed the most to the overall mortality (41% of all death patients with ALF). The causes of death were intracranial hypertension in 3 patients, sepsis in 3, and multiorgan dysfunction in 1 of them. The median age was 38 years (IQR ¼ 30). The average MELD score at admission was 38 6, which was significantly higher than the average of the remaining 26 patients (31 8, P ¼ .02). The highest MELD score achieved (41 7) was also significantly higher for these patients than for the rest (34 9, P ¼ .03). Six patients had HE grades III to IV, 3 had unfavorable etiologies, and 2 had subacute impairment. The referral time was significantly longer in this group (10 days, IQR ¼ 42, minimum 3 and maximum 60) than in those fulfilling LT criteria without contraindications or in those without LT criteria (P ¼ .02; Tables 2 and 3).
and a maximum of 23 days being significantly lower than for the w-KCC/w-CO group (3.5 vs 10, P ¼ .02) and similar to the n-KCC group (3.5 vs 7.5; P ¼ .94). In the w-KCC/n-CO group (n ¼ 22), 10 patients recovered spontaneously without LT (R-list), 5 died on waiting list (D-list), and 7 were transplanted (LT). The mean MELD score at admission was similar in the 3 subgroups. The mean MELD score highest achieved was significantly higher in the D-list subgroup (42 3) than in the R-list group (31 7, P < .001). The R-list subgroup was referred to the LT program within a median of 2 days (IQR ¼ 3), which was significantly shorter than the patients who were transplanted (median of 9 days, IQR ¼ 17, P ¼ .09) if we consider 90% confidence. No statistical differences were demonstrated between R-list and D-list groups (median of 10 days, IQR ¼ 7, P ¼ .14). R-List Subgroup
The patients with a spontaneously recovery (R-list subgroup; n ¼ 10) contributed the most to the overall survival (10 of 16 survivors, 63%). The median age was 45 years (IQR ¼ 15). Four patients had HE grades III to IV. Two patients had unfavorable etiologies, and 2 had subacute impairment. The median time until being delisted for recovery was 4.5 (IQR ¼ 7; minimum ¼ 1 and maximum ¼ 20). The median referral time plus the time on list was 9 days (IQR ¼ 8; minimum ¼ 4 and maximum ¼ 35; Tables 2 and 3).
Patients With Transplant Criteria and No Contraindications
D-List Subgroup
There were 22 patients in the group of patients with transplant criteria and no contraindications (w-KCC/n-CO). Sixtyseven percent of the patients fulfilled LT criteria and had no contraindications, so they were listed for LT. The median age was 44 years with a minimum of 17 and maximum of 64 (IQR ¼ 24), and 14 patients had HE grades III to IV. The mean MELD score at admission was 32 8 and the highest achieved was 36 9. These values were higher than in the nKCC group (at admission 25 3; P ¼ .002 and highest achieved 27 5; P ¼ .01). The MELD values were lower than in the group w-KCC/w-CO (at admission 38 6; P ¼ .04 and highest achieved 41 7; P ¼ .07; statistical significance was tested with a 90% of confidence on the last comparison). The median referral time was 3.5 (IQR ¼ 11) with a minimum of 1
Patients who died on list (D-List subgroup; n ¼ 5) contributed to the overall ALF mortality by 29%. Two died from intracranial hypertension, 2 from multiorgan dysfunction, and the remaining 1 from sepsis. The median age was 43 years. All had HE grades III to IV. Two patients had unfavorable etiologies and 1 showed subacute impairment. The median time on waiting list was 8 days (IQR ¼ 7; minimum ¼ 2 and maximum ¼ 35). The median referral time plus the time until death was 18 days (IQR ¼ 21; minimum ¼ 5 and maximum ¼ 45; Tables 2 and 3). LT Subgroup
Five of the 7 transplanted patients died after surgery (71% of mortality), accounting for 29% of the overall mortality. Two
Table 2. Comparison Data of MELD and Waiting Times Among the 5 Groups Studied MELD at Admission
n-KCC (n ¼ 4) w-KCC/w-CO (n ¼ 7) w-KCC/n-CO (n ¼ 22) LT (n ¼ 7) D-list (n ¼ 5) R-list (n ¼ 10) Total (n ¼ 33)
25 38 32 34 35 30 33
3 6 8 10 9 7 8
Highest MELD Achieved
27 41 36 39 42 31 36
5 7 9 10 3 7 9
RT
7.5 10 3.5 9 10 2 7
(IQR (IQR (IQR (IQR (IQR (IQR (IQR
WLT
¼ ¼ ¼ ¼ ¼ ¼ ¼
3) 42) 11) 17) 7) 3) 12)
6.5 (IQR ¼ 12) 6 (IQR ¼ 17) 8 (IQR ¼ 7) 4.5 (IQR ¼ 7) 3 (IQR ¼ 7)
TT
12 23 18 9
(IQR (IQR (IQR (IQR
¼ ¼ ¼ ¼
20) 24) 21) 8)
Abbreviations: D-list, list-deceased; IQR, interquartile range; LT, transplant patients; MELD, Model for End-Stage Liver Disease; n-KCC, group without transplant criteria according to King College; R-list, recovery spontaneously without LT; RT, referral time; TT, total time; w-KCC/n-CO, patients meeting transplant criteria without contraindications; w-KCC/w-CO, group meeting transplantation criteria but with contraindications for transplantation; WLT, waiting list time.
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Table 3. Characteristics of the Underlying Diseases in the Groups of Patients With ALF Studied (Total n [ 33) Unfavorable Causes
n-KCC (n ¼ 4) w-KCC/w-CO (n ¼ 7) w-KCC/n-CO (n ¼ 22) LT (n ¼ 7) D-list (n ¼ 5) R-list (n ¼ 10)
Encephalopathy Grade III-IV
O’Grady Classification
Age (y)
Yes
No
Yes
No
Hyperacute/Acute
Subacute
41 39
1 3 8 4 2 2
3 4 14 3 3 8
0 6 14 5 5 4
4 1 8 2 0 6
4 5 17 5 4 8
0 2 5 2 1 2
38 37 39
Abbreviations: ALF, acute liver failure; D-list, group of patients that died in waiting list; LT, group of transplanted patients; n-KCC, group without transplant criteria according to King College; R-list, group of patients that recovered spontaneously without liver transplantation and were retired from the list; w-KCC, group meeting transplantation criteria according to King College; w-KCC/n-CO, group meeting transplant criteria without contraindications; w-KCC/w-CO, group meeting transplantation criteria but with contraindications for transplantation.
died from sepsis, 1 from multiorgan dysfunction, 1 from acute myocardial infarction with cardiogenic shock, and the remaining 1 from hypovolemic shock. The 2 surviving patients had an average follow-up of 22 months. The median age was 38 years, and the mean MELD score at transplant was 39 10, which was also the highest MELD score achieved. Five patients had HE grades III to IV. Unfavorable etiologies were present in 4 patients and 2 showed subacute impairment. The median referral time was 9 days (IQR ¼ 17; minimum ¼ 1 and maximum ¼ 23) and patients spent a median of 6 days on the waiting list (IQR ¼ 17; minimum ¼ 2 and maximum ¼ 90), and the median total time from the first consultation to LT was 23 days (IQR ¼ 24; minimum ¼ 3 and maximum 110; Tables 2 and 3). Regarding the mortality determinants after LT, all were found to be higher in patients who died (n ¼ 5) than in those who survived post-LT (n ¼ 2): median total waiting time was 23 vs 21 days, mean MELD score at admission was 38 vs 23, mean MELD score at transplant was 44 vs 26, median age was 48 vs 29, male sex was 1 vs 0, use of vasopressors was 3 patients vs 0, suboptimal donor was 2 cases vs 0. No statistical tests were performed given the small number of patients. DISCUSSION
The 3 most common causes of ALF (viral hepatitis, indeterminate, and autoimmune hepatitis) are similar to others in the region [12]; nevertheless, Uruguay has a surprisingly high incidence of Wilson disease. A decrease in the incidence of viral etiology is expected, given the inclusion of mandatory vaccination of hepatitis A (from 2008) and hepatitis B (from 1999 in the pentavalent vaccine at 1 year of life, and from 2000 to 2012 at 12 years also) and the high vaccination coverage in Uruguay (>95%) [27]. However, there is a pool of patients older than 30 who continue to transmit hepatitis B infection, which could be prevented by universal vaccination. Overall mortality was 52%, higher than the reported in Europe, United States, and Argentina (38%, 33%, and 27%, respectively) [8,9,12]. The mortality of nontransplanted patients was similar: 46% in Uruguay vs 52%
in Europe [8], 57% in the United States [9], and 46% in Argentina [12]. The mortality rate of patients on waiting list was also similar to those in the United States and Argentina (23% vs 22% and 19%, respectively) [9,12]. However, the mortality rate of the transplanted patients was much higher (71% in our series vs 14% in Europe [8], 16% in the United States [9], and 11% in Argentina [12]). Sixty-eight percent of the patients listed for LT were not transplanted. The median waiting time list was 7 days. Therefore, the low applicability of LT (32%) could be related to the delay in the availability of an organ. It is important to determine the prognostic factors that are linked to survival without transplantation to identify which subgroup of patients will improve without it. Patients who recovered without LT were referred earlier than those who were transplanted and achieved lower MELD scores than those who died on list. The minority of these patients had unfavorable etiologies or subacute impairment. Transplanted patients had a significantly longer referral time than those delisted for improvement, and the MELD score at admission was 34. Early referral, even in those who do not initially meet the criteria for transplantation, is a key factor in improving patient survival because it allows specific or highly complex treatment in a specialized unit [1]. It is possible that the delay in the derivation of the transplanted patients led to a deterioration of the clinical status decreasing the probability of survival without transplantation. MELD score greater than 29 at admission was associated with an unfavorable outcome (need for transplantation or death) [12]. The waiting list time of transplanted patients (median of 6 days) was much higher than those reported in the United States (median 3.5 days, range 1e42) [9], Argentina (mean 3.8 days, range 0e8) [12], and Spain (median 39 39 hours) [6]. Transplanted patients as well as those who died on the list had deterioration in their clinical conditions, reflected by the increase in MELD scores, from 34 to 39 and 35 to 42, respectively. In fact, the waiting time of these patients is even longer if we consider the referral time (referral time plus waiting list time of 23 days for transplant patients and 18 days for the deceased). Therefore, the patients who were transplanted in Uruguay due to ALF waited almost a month
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to receive a graft. Prolonged waiting time and high MELD scores could be determinants of post-transplant mortality in these patients. Despite the high mortality in the transplanted group, the LT program met most of the quality international criteria for LT (including survival rates) [28]. However, we cannot evaluate the influence of anesthetic-surgical variables on the high postoperative mortality of ALF in this study. To decreased mortality in LT due to ALF, 2 major facts can be pointed: the need to decrease the waiting times to prevent clinical deterioration and the recognition of those patients who are too sick to transplant to avoid futile transplantation. The decision of who is too sick for LT should involve all members of the multidisciplinary team. The only definitive criteria contraindicating LT is irretrievable brain injury. Unsolved active infection, refractory shock, and low cardiac output, among others, are relative contraindications [1]. Educational strategies for general practitioners to rapidly identify these patients are mandatory. To increase the number of donors in Uruguay and reduce waiting list times, a change in legislation had been applied since September 2013, making all people potentially donors except those who express the wish not to donate in life. The donation rate in Uruguay is one of the highest in Latin America (13.1 donors per million inhabitants) [29,30]. Nevertheless, the population of the country is less than three and a half million, so there was 1 effective donor every 12 days by 2015 [29,30]. Countries with a similar number of inhabitants and donation rates have agreements with neighboring countries with larger populations for emergency transplants. This is the case in New Zealand (4,746,000 inhabitants and 16.8 donors per million inhabitants), which has an agreement with Australia (population of 23,941,000), leading to a waiting list time for ALF patients of 2 days and a transplant survival rate of 77% [31,32]. In the case of Ireland, an agreement was made with the United Kingdom [33]; and the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) have an organ exchange agreement for emergencies between each other, with a payback system [18,34]. Another strategy used in countries with low organ availability is LT with a related living donor (not available in Uruguay), which has shown good results for ALF patients in Asia [35]. CONCLUSION
ALF in Uruguay results in a high mortality rate, which is related to the delay in the referral of patients to the LT center, the highest MELD score, and the highest grade of encephalopathy. The long waiting list time might influence mortality, which may be improved by developing public health policies of organ sharing between countries. REFERENCES [1] Wendon J, Cordobay J, Dhawan A, Larsen FS, Manns M, Nevens F, et al. EASL Clinical Practical Guidelines on the
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ACUTE LIVER FAILURE IN URUGUAY [23] Uruguay en cifras 2014. Instituto Nacional de Estadistica. http://www.ine.gub.uy. [24] Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathyddefinition, nomenclature, diagnosis, and quantification: final report of the Working Party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002;35:716e21. [25] O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993;342:273e5. [26] Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91e6. [27] Uruguay/Ministerio de Salud Pública. Available from www.msp.gub.uy/publicaci%C3%B3n/programa-nacional-devacunaciones-79k. [28] JI H. III Reunión de consenso de la Sociedad Española de Trasplante Hepático (SETH). Hepatitis C, trasplante hepático de donante vivo, calidad de los injertos hepáticos y calidad de los programas de trasplante hepático. Gastroenterol Hepatol 2011;34: 641e59.
471 [29] Newsletter-Transplante Iberoamérica 2016. Sociedad de Trasplante de America Latina y El Caribe. Available from http:// www.stalyc.net. [30] Registro Donantes INDT. Estadisticas Y Registro Nacional De Donantes. Evolucion De Los Registros Periodo 2005-2014 Available from https://www.indt.gub.uy/uploads/estadisticas_ organosytejidos.pdf [31] Gane E, McCall J, Streat S, Gunn K, Yeong ML, Fitt S, et al. Liver transplantation in New Zealand: the first four years. N Z Med J 2002;115:1e13. [32] McCaughan GW, Munn SR. Liver transplantation in Australia and New Zealand. Liver Transplant 2016;22:830e8. [33] Iqbal M, Elrayah EA, Traynor O, McCormick PA. Liver transplantation in Ireland. Liver Transplant 2016;22:1014e8. [34] Exchange payback rules. http://www.scandiatransplant.org/ organallocation/NLTG_Exchange_payback_rules_01_dec_2016.pdf. [35] Park SJ, Lim YS, Hwang S, Heo NY, Lee HC, Suh DJ, et al. Emergency adult-to-adult living-donor liver transplantation for acute liver failure in a hepatitis B virus endemic area. Hepatology 2010;51:903e11.
ABSTRACT Background. Acute liver failure (ALF) is a syndrome with high mortality. Objective. Describe characteristics and outcomes of patients with ALF in Uruguay, and identify factors associated with mortality. Methods. A retrospective analysis of 33 patients with ALF was performed between 2009 and 2017. Results. The patients’ median age was 43 years, and 64% were women. Average Model for End-Stage Liver Disease (MELD) score at admission was 33. The median referral time to the liver transplant (LT) center was 7 days. The most common etiologies were viral hepatitis (27%), indeterminate (21%), autoimmune (18%), and Wilson disease (15%). Overall mortality was 52% (71% of transplanted and 46% of nontransplanted patients). Dead patients had higher referral time (10 vs 4 days, P ¼ .008), higher MELD scores at admission (37 vs 28) and highest achieved MELD scores (42 vs 29; P < .001), and higher encephalopathy grade III to IV (94% vs 25%, P < .001) than survivors. Patients without LT criteria (n ¼ 4) had lower MELD score at admission (25 vs 34, P ¼ .001) and highest achieved MELD score (27 vs 37, P ¼ .008) compared with the others. Patients with LT criteria but contraindications (n ¼ 7) had higher MELD scores at admission (38 vs 31, P ¼ .02), highest achieved MELD scores (41 vs 34, P ¼ .03), and longer referral time (10 days) than those without contraindications (3.5 days) or those without LT criteria (7.5 days, P ¼ .02). Twenty-two patients were listed; LT was performed in 7, with a median time on waiting list of 6 days. Conclusions. ALF in Uruguay has high mortality associated with delayed referral to the LT center, MELD score, and encephalopathy. The long waiting times to transplantation might influence mortality.
A
CUTE LIVER FAILURE (ALF) is a syndrome characterized by the development of coagulopathy and encephalopathy in patients without previous liver disease [1]. The incidence is low: 2000 cases per year in the United States (estimated at 6.2 per million inhabitants per year) [2,3], 1 to 8 cases per million inhabitants per year in the United Kingdom [4,5], and 1.4 per million inhabitants per year in Spain [6]. ALF has a high mortality rate, although the prognosis has dramatically improved since the introduction of liver transplantation (LT) in the late 1980s along with advances in critical care. In the 1970s, the global mortality rate was 83% ª 2017 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 465e471 (2018)
to 85% [7,8], and currently the rates are 38% in Europe [8] (42% in Spain [6]) and 33% in the United States [9]. There was a difference in the survival of patients who did not receive a transplant compared with those who did in Europe between 2004 and 2008 (48% and 86%, respectively)
*Address correspondence to Victoria Mainardi, MD, José Felix Zubillaga 1133/1, CP11300, Montevideo, Uruguay. Tel: þ598 99 59 74 86. E-mail: [email protected] or victoria_mainardi@ hotmail.com 0041-1345/18 https://doi.org/10.1016/j.transproceed.2017.12.037
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[8], as well as in the United States between 1998 and 2001 (43% and 84%, respectively) [9]. ALF accounted for 8% of indications for LT in Europe. Survival rates at 1, 3, and 5 years have improved over the past 20 years and are currently 79%, 75%, and 72%, respectively. However, survival is lower than that of elective transplant [10]. In the United States, ALF accounted for 3.3% of the indications for LT, and the survival rate at 1 year is above 80% [3,11]. The utilization of LT in ALF varies between different countries (18.2% in Europe [7], 29% in the United States [9], and 54% in Argentina [12]), transplant centers in the same country, and different etiologies [1]. In Europe the most common cause is drug-induced hepatotoxicity [8]; in United Kingdom, induced by Paracetamol [4], and in other areas such as Spain induced by non-Paracetamol drugs [6]. In the United States, Paracetamol hepatotoxicity is also the leading cause [9]. Viral hepatitis is the most frequent cause in South America [12], Asia [13,14], and Africa [15]. The following factors are recognized to contribute to a poor prognosis in ALF: advanced age, unfavorable etiologies (such as indeterminate, non-Paracetamol drug hepatotoxicity, and Wilson disease), subacute impairment, advanced encephalopathy, severe liver injury, extrahepatic failure (particularly renal failure), and late referral to a specialized unit [1,8,9,12,16,17]. The prognosis after listing for LT depends on the availability of a compatible donor organ, which depends on the number of available donors (donation rate and population) and the organ allocation system [18]. Mortality determinants after LT in ALF patients have been studied. Data from the European Liver Transplant Register identify the following determinants: recipient age >50 years and male sex, donor age >60 years, and incompatible ABO group [10]. The United Network for Organ Sharing cites the following determinants: recipient age >50 years, body mass index 30 kg/m2, creatinine >2 mg/dL, and history of life support [19]. King College Hospital identifies 4 variables: age of the recipient >45 years, requirement of vasopressors, and suboptimal donor defined by the presence of 2 of the following: age >60 years, steatosis, nonidentical ABO group, and reduced graft [20]. Other factors that have been shown to be associated with post-transplant mortality are elevated Model for End-Stage Liver Disease (MELD) scores [21] and a prolonged waiting list time [22]. Uruguay has a population of 3,440,000 (in 2014) [23] and has a single National Liver Transplant Program, which operates in the Military Hospital, and is an adult-only program. There is only one national waiting list; ALF has the highest priority, categorized as an emergency. Our objective is to describe the characteristics and outcomes of patients with ALF in Uruguay and identify the possible factors associated with mortality.
MAINARDI, RANDO, OLIVARI ET AL Program between April 2009 and April 2017 was performed. Approval from the Institutional Research Board was obtained. All enrolled patients met entry criteria for ALF: presence of coagulopathy (international normalized ratio 1.5) and any grade of hepatic encephalopathy (HE) within 26 weeks of the onset of symptoms, without underlying liver disease. Patients with Wilson disease, hepatitis B virus infection, or autoimmune hepatitis with cirrhosis were included if their disease had been recognized for <26 weeks [7]. Demographic, clinical, etiologic, laboratory, therapeutic, organizational data (referral time defined as the period between the first medical appointment and the contact with the LT program, waiting list time), and outcomes (mortality at discharge) were collected. The HE was graded from I to IV according to the West Heaven criteria [24]. ALF was classified as hyperacute, acute, or subacute impairment according to O’Grady classification [25]. Etiologic diagnoses were made based on accepted diagnostic criteria, including clinical history, laboratory values, imaging studies, and, in some cases, histologic characteristics. ALF was considered indeterminate when clinical, laboratory evaluation including toxicologic screening, serologic markers for viruses and antibodies, imaging studies, and histology (when available) were inconclusive. The management of the patients followed published guidelines. Medical treatment measures included prevention of hypoglycemia, bacterial and fungal infections, upper gastrointestinal tract bleeding and renal failure, treatment of HE, correction of blood volume and electrolyte and acid-base disorders, administration of coagulation factors if active bleeding or performing invasive procedures, and specific etiologic treatment if was available. Patients with HE grade II were given N-acetylcysteine. Extracorporeal hepatic support (Prometheus, Fresenius Medical Care, Germany) was performed in 2 patients. Candidacy for LT was determined according to the King’s College criteria (KCC) proposed by O’Grady et al [16]. The MELD score [26] was determined. The following contraindications for LT were defined: irreversible brain injury, unsolved active infection, multiple organ dysfunction with more than 3 organs compromised, extrahepatic cancer, and severe extrahepatic diseases that could not be solved with combined transplantation. In the patients who were transplanted, orthotopic LT of cadaveric donor was performed.
Statistical Analysis Numerical variables are expressed as means and standard deviations in case of normal variables and median and interquartile range (IQR) in case of non-normal variables. The statistical significance of differences between groups was calculated using a Student t test for independent samples in the case of normal variables and a Wilcoxon rank test in case of non-normal variables. c2 Test with Yates correction was used for categorical variables, which are expressed in percentages. The statistical software used was R (version 3.4.0; R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was tested with a 95% of confidence (exceptions were clarified on the text).
RESULTS METHODS Patients and Methods A retrospective analysis of 33 charts of adult patients (older than 14 years) hospitalized with ALF at the National Liver Transplant
Thirty-three patients were included. The estimated incidence of ALF during the study period was 1.2 cases per million inhabitants per year (this may be underestimated due to patients not being referred to the LT program).
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During this period 148 LTs were performed, with ALF accounting for 5% of the indications.
ALF N=33
Demographic and Clinical Characteristics
The median age was 43 years (IQR ¼ 27; minimum ¼ 17 and maximum ¼ 64), and 64% of the patients were women. According to O’Grady classification, 12 were hyperacute (36%), 14 were acute (42%), and 7 were subacute (21%). The mean MELD score at admission was 33 8, and the mean highest MELD score achieved was 36 9. Twenty patients (61 %) had HE grade III to IV. The median referral time was 7 days (IQR ¼ 12), with a minimum of 0 and maximum of 60 days. The median waiting list time was 7 days (IQR ¼ 12), with a minimum of 1 and maximum of 90 days. The most frequent cause of ALF was viral hepatitis (27%, hepatitis B in 8 cases and hepatitis A in 1 case). Indetermined ALF accounted for 7 cases (21%), autoimmune hepatitis 6 cases (18%), and Wilson disease 5 cases (15%). Hepatotoxicity accounted for 2 patients (6%): one for nonsteroidal antiinflammatory drugs and the other for Amanita phalloides poisoning. No paracetamol hepatotoxicity was reported. Budd-Chiari syndrome, ischemic hepatitis, heat shock, and graft-vs-host disease each accounted for 1 case (3%). Outcomes
Outcomes are depicted in Fig 1. Four patients did not meet KCC. Of the 29 patients who fulfilled criteria, 7 had contraindications for LT. Twenty-two patients were listed: in 7 cases (21% of the total ALF) LT was performed, 10 patients recovered without LT, and 5 died on waiting list. The overall mortality was 52% (17 patients). Mortality in the transplanted group of patients was 71% (5 of 7 patients) and in the nontransplanted group was 46% (12 of 26 patients; 7 patients had contraindications for LT and 5 died while waiting for a graft). The mortality of patients on the waiting list was 23%. The overall survival was 48% (16 patients). In 2 patients, LT was performed. Fourteen patients survived without LT, 4 never met KCC, and 10 met the criteria at admission but improved with medical treatment, so they were delisted.
n-KCC
w-KCC N=29
N=4 4 survived
w-KCC / w-CO N=7
w-KCC / n-CO N=22
7 died
LT – N = 7
5 died 2 survived R-list - N = 10
10 survived D-list – N = 5 5 died
Fig 1. Groups and outcomes of the 33 patients included in this study. ALF, acute liver failure; D-list, group of patients that died in waiting list; LT, group of transplanted patients; n-KCC, group without transplant criteria according to King College; R-list, group of patients that recovered spontaneously without liver transplantation and were retired from the list; w-KCC, group meeting transplantation criteria according to King College; w-KCC/n-CO, group meeting transplant criteria without contraindications; w-KCC/w-CO, group meeting transplantation criteria but with contraindications for transplantation.
did not meet emergency transplant criteria at admission or during the evolution. All survived (0% mortality). The median age was 35 (IQR ¼ 22). The mean MELD score at admission (25 3) and the highest achieved MELD score (27 5) were lower in this group of patients than in the remaining 29 cases (34 8 at admission, P ¼ .001; and 37 8 highest score, P ¼ .008). None of the patients presented HE grades III or IV. Only one had an unfavorable etiology,
Variables Associated With Mortality
Table 1 shows the variables associated with mortality. Patients who died (with or without LT) had significantly higher MELD scores at admission (mean 37 vs 28) and highest achieved (mean 42 vs 29; P < .001 in both cases) and a higher proportion of HE grades III to IV than the survivors (94% vs 25%, P < .001). The proportion of unfavorable etiologies and subacute impairment was higher among dead patients, but no significance could be demonstrated. Patients who died had a longer referral time than those who survived (median 10 vs 4 days, P ¼ .008).
Table 1. Factors Associated With Poor Prognosis of ALF in the Groups of Dead Patients Death (n ¼ 17)
Alive (n ¼ 16)
P Value*
43 16 (94%)
41 4 (25%)
.39 <.001
9 (53%) 5 (29%) 37 42 10
4 (25%) 2 (13%) 28 29 4
.20 .45 <.001 <.001 .008
Group Not Meeting Criteria for Transplantation
Median age (y) Encephalopathy grades III to IV, n (%) Unfavorable etiology, n (%) Subacute impairment, n (%) Mean MELD at admission Highest MELD achieved Median referral time (d)
The group not meeting criteria for transplantation (n-KCC) included 4 patients. Twelve percent of patients with ALF
Abbreviations: ALF, acute liver failure; MELD, Model for End-Stage Liver Disease. *In all cases the P values refer to a one-sided test.
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MAINARDI, RANDO, OLIVARI ET AL
and none had subacute impairment. Median referral time was 7.5 days (IQR ¼ 3), with a minimum of 0 and a maximum of 13 (Tables 2 and 3). Group Meeting Transplantation Criteria But With Contraindications
Seven patients comprised the group meeting transplantation criteria but with contraindications (w-KCC/w-CO). Twentyone percent of the patients fulfilled transplant criteria but had contraindications. These contraindications were related to ALF in 6 patients and in 1 patient was severe cardiovascular comorbidity. All died (100% mortality). This group contributed the most to the overall mortality (41% of all death patients with ALF). The causes of death were intracranial hypertension in 3 patients, sepsis in 3, and multiorgan dysfunction in 1 of them. The median age was 38 years (IQR ¼ 30). The average MELD score at admission was 38 6, which was significantly higher than the average of the remaining 26 patients (31 8, P ¼ .02). The highest MELD score achieved (41 7) was also significantly higher for these patients than for the rest (34 9, P ¼ .03). Six patients had HE grades III to IV, 3 had unfavorable etiologies, and 2 had subacute impairment. The referral time was significantly longer in this group (10 days, IQR ¼ 42, minimum 3 and maximum 60) than in those fulfilling LT criteria without contraindications or in those without LT criteria (P ¼ .02; Tables 2 and 3).
and a maximum of 23 days being significantly lower than for the w-KCC/w-CO group (3.5 vs 10, P ¼ .02) and similar to the n-KCC group (3.5 vs 7.5; P ¼ .94). In the w-KCC/n-CO group (n ¼ 22), 10 patients recovered spontaneously without LT (R-list), 5 died on waiting list (D-list), and 7 were transplanted (LT). The mean MELD score at admission was similar in the 3 subgroups. The mean MELD score highest achieved was significantly higher in the D-list subgroup (42 3) than in the R-list group (31 7, P < .001). The R-list subgroup was referred to the LT program within a median of 2 days (IQR ¼ 3), which was significantly shorter than the patients who were transplanted (median of 9 days, IQR ¼ 17, P ¼ .09) if we consider 90% confidence. No statistical differences were demonstrated between R-list and D-list groups (median of 10 days, IQR ¼ 7, P ¼ .14). R-List Subgroup
The patients with a spontaneously recovery (R-list subgroup; n ¼ 10) contributed the most to the overall survival (10 of 16 survivors, 63%). The median age was 45 years (IQR ¼ 15). Four patients had HE grades III to IV. Two patients had unfavorable etiologies, and 2 had subacute impairment. The median time until being delisted for recovery was 4.5 (IQR ¼ 7; minimum ¼ 1 and maximum ¼ 20). The median referral time plus the time on list was 9 days (IQR ¼ 8; minimum ¼ 4 and maximum ¼ 35; Tables 2 and 3).
Patients With Transplant Criteria and No Contraindications
D-List Subgroup
There were 22 patients in the group of patients with transplant criteria and no contraindications (w-KCC/n-CO). Sixtyseven percent of the patients fulfilled LT criteria and had no contraindications, so they were listed for LT. The median age was 44 years with a minimum of 17 and maximum of 64 (IQR ¼ 24), and 14 patients had HE grades III to IV. The mean MELD score at admission was 32 8 and the highest achieved was 36 9. These values were higher than in the nKCC group (at admission 25 3; P ¼ .002 and highest achieved 27 5; P ¼ .01). The MELD values were lower than in the group w-KCC/w-CO (at admission 38 6; P ¼ .04 and highest achieved 41 7; P ¼ .07; statistical significance was tested with a 90% of confidence on the last comparison). The median referral time was 3.5 (IQR ¼ 11) with a minimum of 1
Patients who died on list (D-List subgroup; n ¼ 5) contributed to the overall ALF mortality by 29%. Two died from intracranial hypertension, 2 from multiorgan dysfunction, and the remaining 1 from sepsis. The median age was 43 years. All had HE grades III to IV. Two patients had unfavorable etiologies and 1 showed subacute impairment. The median time on waiting list was 8 days (IQR ¼ 7; minimum ¼ 2 and maximum ¼ 35). The median referral time plus the time until death was 18 days (IQR ¼ 21; minimum ¼ 5 and maximum ¼ 45; Tables 2 and 3). LT Subgroup
Five of the 7 transplanted patients died after surgery (71% of mortality), accounting for 29% of the overall mortality. Two
Table 2. Comparison Data of MELD and Waiting Times Among the 5 Groups Studied MELD at Admission
n-KCC (n ¼ 4) w-KCC/w-CO (n ¼ 7) w-KCC/n-CO (n ¼ 22) LT (n ¼ 7) D-list (n ¼ 5) R-list (n ¼ 10) Total (n ¼ 33)
25 38 32 34 35 30 33
3 6 8 10 9 7 8
Highest MELD Achieved
27 41 36 39 42 31 36
5 7 9 10 3 7 9
RT
7.5 10 3.5 9 10 2 7
(IQR (IQR (IQR (IQR (IQR (IQR (IQR
WLT
¼ ¼ ¼ ¼ ¼ ¼ ¼
3) 42) 11) 17) 7) 3) 12)
6.5 (IQR ¼ 12) 6 (IQR ¼ 17) 8 (IQR ¼ 7) 4.5 (IQR ¼ 7) 3 (IQR ¼ 7)
TT
12 23 18 9
(IQR (IQR (IQR (IQR
¼ ¼ ¼ ¼
20) 24) 21) 8)
Abbreviations: D-list, list-deceased; IQR, interquartile range; LT, transplant patients; MELD, Model for End-Stage Liver Disease; n-KCC, group without transplant criteria according to King College; R-list, recovery spontaneously without LT; RT, referral time; TT, total time; w-KCC/n-CO, patients meeting transplant criteria without contraindications; w-KCC/w-CO, group meeting transplantation criteria but with contraindications for transplantation; WLT, waiting list time.
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Table 3. Characteristics of the Underlying Diseases in the Groups of Patients With ALF Studied (Total n [ 33) Unfavorable Causes
n-KCC (n ¼ 4) w-KCC/w-CO (n ¼ 7) w-KCC/n-CO (n ¼ 22) LT (n ¼ 7) D-list (n ¼ 5) R-list (n ¼ 10)
Encephalopathy Grade III-IV
O’Grady Classification
Age (y)
Yes
No
Yes
No
Hyperacute/Acute
Subacute
41 39
1 3 8 4 2 2
3 4 14 3 3 8
0 6 14 5 5 4
4 1 8 2 0 6
4 5 17 5 4 8
0 2 5 2 1 2
38 37 39
Abbreviations: ALF, acute liver failure; D-list, group of patients that died in waiting list; LT, group of transplanted patients; n-KCC, group without transplant criteria according to King College; R-list, group of patients that recovered spontaneously without liver transplantation and were retired from the list; w-KCC, group meeting transplantation criteria according to King College; w-KCC/n-CO, group meeting transplant criteria without contraindications; w-KCC/w-CO, group meeting transplantation criteria but with contraindications for transplantation.
died from sepsis, 1 from multiorgan dysfunction, 1 from acute myocardial infarction with cardiogenic shock, and the remaining 1 from hypovolemic shock. The 2 surviving patients had an average follow-up of 22 months. The median age was 38 years, and the mean MELD score at transplant was 39 10, which was also the highest MELD score achieved. Five patients had HE grades III to IV. Unfavorable etiologies were present in 4 patients and 2 showed subacute impairment. The median referral time was 9 days (IQR ¼ 17; minimum ¼ 1 and maximum ¼ 23) and patients spent a median of 6 days on the waiting list (IQR ¼ 17; minimum ¼ 2 and maximum ¼ 90), and the median total time from the first consultation to LT was 23 days (IQR ¼ 24; minimum ¼ 3 and maximum 110; Tables 2 and 3). Regarding the mortality determinants after LT, all were found to be higher in patients who died (n ¼ 5) than in those who survived post-LT (n ¼ 2): median total waiting time was 23 vs 21 days, mean MELD score at admission was 38 vs 23, mean MELD score at transplant was 44 vs 26, median age was 48 vs 29, male sex was 1 vs 0, use of vasopressors was 3 patients vs 0, suboptimal donor was 2 cases vs 0. No statistical tests were performed given the small number of patients. DISCUSSION
The 3 most common causes of ALF (viral hepatitis, indeterminate, and autoimmune hepatitis) are similar to others in the region [12]; nevertheless, Uruguay has a surprisingly high incidence of Wilson disease. A decrease in the incidence of viral etiology is expected, given the inclusion of mandatory vaccination of hepatitis A (from 2008) and hepatitis B (from 1999 in the pentavalent vaccine at 1 year of life, and from 2000 to 2012 at 12 years also) and the high vaccination coverage in Uruguay (>95%) [27]. However, there is a pool of patients older than 30 who continue to transmit hepatitis B infection, which could be prevented by universal vaccination. Overall mortality was 52%, higher than the reported in Europe, United States, and Argentina (38%, 33%, and 27%, respectively) [8,9,12]. The mortality of nontransplanted patients was similar: 46% in Uruguay vs 52%
in Europe [8], 57% in the United States [9], and 46% in Argentina [12]. The mortality rate of patients on waiting list was also similar to those in the United States and Argentina (23% vs 22% and 19%, respectively) [9,12]. However, the mortality rate of the transplanted patients was much higher (71% in our series vs 14% in Europe [8], 16% in the United States [9], and 11% in Argentina [12]). Sixty-eight percent of the patients listed for LT were not transplanted. The median waiting time list was 7 days. Therefore, the low applicability of LT (32%) could be related to the delay in the availability of an organ. It is important to determine the prognostic factors that are linked to survival without transplantation to identify which subgroup of patients will improve without it. Patients who recovered without LT were referred earlier than those who were transplanted and achieved lower MELD scores than those who died on list. The minority of these patients had unfavorable etiologies or subacute impairment. Transplanted patients had a significantly longer referral time than those delisted for improvement, and the MELD score at admission was 34. Early referral, even in those who do not initially meet the criteria for transplantation, is a key factor in improving patient survival because it allows specific or highly complex treatment in a specialized unit [1]. It is possible that the delay in the derivation of the transplanted patients led to a deterioration of the clinical status decreasing the probability of survival without transplantation. MELD score greater than 29 at admission was associated with an unfavorable outcome (need for transplantation or death) [12]. The waiting list time of transplanted patients (median of 6 days) was much higher than those reported in the United States (median 3.5 days, range 1e42) [9], Argentina (mean 3.8 days, range 0e8) [12], and Spain (median 39 39 hours) [6]. Transplanted patients as well as those who died on the list had deterioration in their clinical conditions, reflected by the increase in MELD scores, from 34 to 39 and 35 to 42, respectively. In fact, the waiting time of these patients is even longer if we consider the referral time (referral time plus waiting list time of 23 days for transplant patients and 18 days for the deceased). Therefore, the patients who were transplanted in Uruguay due to ALF waited almost a month
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to receive a graft. Prolonged waiting time and high MELD scores could be determinants of post-transplant mortality in these patients. Despite the high mortality in the transplanted group, the LT program met most of the quality international criteria for LT (including survival rates) [28]. However, we cannot evaluate the influence of anesthetic-surgical variables on the high postoperative mortality of ALF in this study. To decreased mortality in LT due to ALF, 2 major facts can be pointed: the need to decrease the waiting times to prevent clinical deterioration and the recognition of those patients who are too sick to transplant to avoid futile transplantation. The decision of who is too sick for LT should involve all members of the multidisciplinary team. The only definitive criteria contraindicating LT is irretrievable brain injury. Unsolved active infection, refractory shock, and low cardiac output, among others, are relative contraindications [1]. Educational strategies for general practitioners to rapidly identify these patients are mandatory. To increase the number of donors in Uruguay and reduce waiting list times, a change in legislation had been applied since September 2013, making all people potentially donors except those who express the wish not to donate in life. The donation rate in Uruguay is one of the highest in Latin America (13.1 donors per million inhabitants) [29,30]. Nevertheless, the population of the country is less than three and a half million, so there was 1 effective donor every 12 days by 2015 [29,30]. Countries with a similar number of inhabitants and donation rates have agreements with neighboring countries with larger populations for emergency transplants. This is the case in New Zealand (4,746,000 inhabitants and 16.8 donors per million inhabitants), which has an agreement with Australia (population of 23,941,000), leading to a waiting list time for ALF patients of 2 days and a transplant survival rate of 77% [31,32]. In the case of Ireland, an agreement was made with the United Kingdom [33]; and the 5 Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) have an organ exchange agreement for emergencies between each other, with a payback system [18,34]. Another strategy used in countries with low organ availability is LT with a related living donor (not available in Uruguay), which has shown good results for ALF patients in Asia [35]. CONCLUSION
ALF in Uruguay results in a high mortality rate, which is related to the delay in the referral of patients to the LT center, the highest MELD score, and the highest grade of encephalopathy. The long waiting list time might influence mortality, which may be improved by developing public health policies of organ sharing between countries. REFERENCES [1] Wendon J, Cordobay J, Dhawan A, Larsen FS, Manns M, Nevens F, et al. EASL Clinical Practical Guidelines on the
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