Acute liver failure (ALF) is a complex medical condition defined as a rapid development of liver failure characterized by impaired hepatic synthesis, especially coagulation factors, associated with encephalopathy [1]. Due to the substantial advances in medical management of ALF, a significant improvement in spontaneous survival of 10–20% to about 40% has been achieved [2–4]. Epidemiological studies have shown a marked geographical difference in relation to prognosis, etiology and evolution of ALF [5].

A recent study from the Acute Liver Failure Study Group (ALFSG) described that paracetamol toxicity and idiosyncratic drug reactions remain as the most common causes of ALF in the United States [2]. In the UK, paracetamol related admissions to liver units fell 40% after implementing drug sales-restriction [3]. Information on the etiology and outcome of patients with ALF in Latin America is scarce. In Argentina we described acute hepatitis B virus (HBV) infection and autoimmune hepatitis as the two most common causes of ALF and, remarkably, no cases of paracetamol poisoning were reported [6]. This study only included six liver transplant centers for a 6-year period. The liver transplantation field in Argentina underwent major changes after the expansion in the number of liver transplant programs with a disproportionate increase in the number of patients on the waiting list compared to the number of donors. Moreover, the vaccine schedules were modified with the introduction of the vaccine against hepatitis A virus (HAV) and HBV but the long-term impact of this measure in the adult population has not been investigated.

Therefore, the aim of this study was to evaluate whether changes in outcomes and etiologies have occurred in patients listed with ALF using the Argentinean national institute for organ allocation and to identify risk factors for poor outcome in this population.

This was a retrospective study of adult patients with ALF listed for orthotopic liver transplantation (OLT) in Argentina from January 1998 to September 2016. The study included adult patients (16 years or older) listed with ALF as emergency status. All enrolled patients met entry criteria for ALF: presence of coagulopathy (international normalized ratio [INR] ≥1.5 or prothrombin index <50%) and any grade of hepatic encephalopathy within 26 weeks of the first symptoms without known underlying liver disease [7]. Patients with Wilson disease, vertically-acquired HBV or autoimmune hepatitis with cirrhosis were included if their disease was recognized for <26 weeks. Etiologic diagnosis was made according to international guidelines at each study center based on clinical history, imaging studies, laboratory values and, in some cases, histopathologic characteristics [1,7]. To confirm the diagnosis of autoimmune hepatitis, the simplified criteria was retrospectively applied, those patients who presented a score ≥6 were identified as autoimmune hepatitis [8]. However, autoantibodies were only considered positive at significant titers (≥1/80). ALF was considered to be indeterminate when extensive clinical and laboratory evaluation (including toxicology screens, autoantibodies and serologic markers for viral hepatitis), as well as imaging studies were inconclusive. Even though patient management and candidacy for OLT was determined at each site. Listing for transplantation criteria were uniform and followed published clinical guidelines [1,7]. Argentina has 21 liver transplant centers, of which 15 are private institutions. A single transplant list is used. The actual donation rate is 10.77 donors per million inhabitants [9]. During both periods, patients meeting criteria for ALF and who were admitted in an ICU were eligible for “Emergency Status” which gave them preference in organ allocation over all forms of chronic liver disease irrespective of time spent waiting for an organ. Also eligible for this category were patients with primary non-function or acute hepatic thrombosis (<7 days following OLT).

Data were obtained from the database of the Instituto Nacional Central Unico Coordinador de Ablación e Implante (INCUCAI), which is the national institute for organ allocation. Since July 2005, after MELD allocation implementation, an internet-based collection system, Sistema Nacional de Información y Trasplante de la República Argentina (SINTRA), was established to capture directly pre- and post-OLT data from all centers.

During the pre-SINTRA era data collection was limited to the following variables: recipient age, gender and type of donor (cadaveric or living). After the implementation of SINTRA, the donor variables were age, gender, type of donor; recipient variables were: age, gender, total bilirubin, serum creatinine, INR, weight, height, etiology of ALF and donor/recipient blood group matching (compatible, incompatible); graft variables were: type of graft (full size, split liver, living donor); variables related to liver transplant technique were: cold ischemic time, warm ischemia time, type of transplant (orthotopic, heterotopic and auxiliary). These parameters were compared in survivors and non-survivors to identify independent predictors of death on the waiting-list and following OLT. The SINTRA database does not include variables related to intensive care management (i.e. ventilation, renal support and intracranial pressure monitoring). Model for end-stage liver disease (MELD) score was determined as described [10]. Although SINTRA has a systematic quality control for data capture, we contacted each center and validated all data presented for the study. Validation included replacement of missing data, review of inconsistencies, and update of dates of follow up. All corrections were returned to SINTRA database.

Survival and transplant outcomes were estimated in two time periods, early period (January 2, 1998 to July 11, 2005), and later period (July 12, 2005 to September 16, 2016). This cut-off was selected according to the pre- and post-SINTRA implementation given that in the SINTRA era we account for more detailed information regarding donor and recipient characteristics.

The study was conducted according to the principles of the Declaration of Helsinki. The local institutional review board of each center approved the study. All procedures followed were in accordance with STROBE guidelines for cohort studies and complied with the ethical standards of the responsible committee on human experimentation and with the Helsinski Declaration 1975, as revised in 2008 [11]. The Institutional Review Board at the Hospital Universitario Austral approved the study.

We used the INCUCAI database to analyze the etiologies and outcomes solely of patients listed for ALF. To the best of our knowledge, this is the largest published cohort of patients listed for ALF in Latin America, and gives a comprehensive overview of the evolution and outcomes of ALF in Argentina. The main etiologies of ALF in Argentina were indeterminate and autoimmune hepatitis. We described that survival of patients with ALF on the waiting list and after OLT has significantly improved over the last years. After performing a competing risk analysis considering OLT as the competing event we found that indeterminate cause of ALF was associated with worse outcome and possible autoimmune hepatitis with might be associated with improved survival. In those who underwent OLT, we identified prolonged cold ischemia time and serum creatinine to be independently associated with poor outcomes.

It is important that physicians taking care of these complex patients know detailed ALF epidemiology in their regions in order to allow a prompt and proper diagnosis and a better management of their patients [12]. We confirm previous reports regarding the low incidence of paracetamol-related ALF in our country, accounting for only 0.5% of cases [6,13]. These results clearly contrast with those reported by the ALFSG and King's College were almost half of the patients presented paracetamol-toxicity [2,3]. Our data showed that indeterminate or cryptogenic cause is the major etiology in Argentina accounting for 28% of cases, similar findings to those reported in Spain (32%) and Germany (24%) but inferior to those described by the European Liver Transplant Registry (43%) [4,14,15]. Efforts should be made to ensure that the etiology is correctly diagnosed in a timely fashion using measures beyond the usual autoimmune and hepatitis serologies. In this sense, the use of paracetamol-cys adducts measurements to confirm or deny that paracetamol is the cause of liver injury might not be necessary in our area. On the other hand, hepatitis E was not routinely evaluated, so the real prevalence of this infection remains unknown. Correct diagnosis of patients with fulminant presentation of autoimmune hepatitis is challenging. These patients often have elevated γ-globulin levels and positive autoantibodies, but these can be absent in a proportion of cases [1,16]. Autoimmune hepatitis is a common cause of end-stage liver disease and ALF in Argentina [6,17]. In accordance with these reports, autoimmune hepatitis was one of the most prevalent etiologies of ALF in our study. Patients with autoimmune hepatitis presented with better spontaneous survival when compare to indeterminate causes. This interesting finding could be associated to the fact that autoimmune hepatitis can benefit from the early use of corticosteroids. Whilst the risk and benefits of corticosteroid administration in this scenario should be weighed carefully, early diagnosis and treatment of these patients might preclude OLT or death [18,19].

Identifying patients with ALF at risk of death without OLT is the most challenging assessment in this setting. Multiple prognostic systems have been developed to aid decision making for OLT. In our study we solely focused on patients with ALF who were listed. Thus, using traditional ALF prognostic scores in this population to identify patients who will benefit from OLT can represent a bias. To gain a better understanding of factors associated with death in our cohort we performed a competing risk regression analysis including OLT as the competing event. In the final model we found indeterminate cause to be strongly associated with detrimental outcome. When compared to other etiologies, patients with indeterminate cause have worse survival after being listed, independently if they were transplanted or not. We believe this is an interesting finding that will help transplant teams to specially focus on these patients, not only regarding medical support but also to make all the possible efforts to try to identify the etiology. Recently, the ALFSG described the evolution of patients listed for ALF and stratified the outcomes by their four main etiologies [20]. Despite a great proportion of the ALFSG patients presented paracetamol toxicity they reported that patients with non-paracetamol intoxication were more likely to receive a transplant and less likely to die without transplant. This is in line with our findings. Patients with autoimmune hepatitis presented a trend toward better survival. As aforementioned, we speculate this is a consequence of a more indolent presentation characterized by a prolonged interval between jaundice and encephalopathy allowing physicians to install medical therapies (corticosteroids) and to eventually be transplanted. The risk in this scenario is that patients with autoimmune hepatitis can be “overtransplanted” given the longer time they can remain on the waiting list.

Recipient and donor factors associated with poor post-OLT outcomes are similar in transplants performed electively or secondary to ALF. In the ALF setting, variables better predicting survival without transplant are not the same as those predicting survival after OLT. Recipient clinical condition and graft quality directly impact the outcome of transplantation. Intensive care support, increased age and BMI are well-identified factors associated with poor outcome after OLT for ALF [4,21,22]. In our series, prolonged cold ischemia time and creatinine were independent factors associated with reduced survival after OLT. Prolonged cold ischemia time is a well-established risk factor included in the donor risk index for graft failure [23]. Ischemic injury damages the liver graft at the cellular level and may lead to primary nonfunction, ischemic cholangiopathy and delayed graft function. Each additional hour of cold ischemia time is associated with an additional 1% increased risk of graft loss [23]. On the other hand, renal dysfunction is an indicator of multisystemic disorder triggered by ALF, as well marked activation of systemic inflammatory response that can extend into the posttransplant period. We acknowledge that relevant variables such as encephalopathy grade, vasopressors or ventilatory support are missing in the model. Thus, we recommend careful interpretations of our results given that many confounders were not adjusted in our analysis.

As with all registry-based observational studies, the results of this study are subject to certain limitations. First, our study is retrospective and cannot account for inherent and undocumented patients characteristics. However, we checked for missing values and inconsistencies, and queries were referred to the participating institution. In addition, we only included patients listed for OLT so our results can overestimate the need of liver transplantation. Lastly, using the INCUCAI database, we are dependent on the variables and definitions present in the data set, and important information such as detailed intensive care management and hepatic encephalopathy grade are missing.

In summary, this analysis of the INCUCAI database confirms that indeterminate cause is the most frequent etiology in our population and it is associated with worse outcome irrespective of accessing OLT when compared to autoimmune hepatitis or other etiologies. We consider this information is critical to assist physicians and other healthcare providers in the clinical evaluation and therapeutic decision-making processes. Noticeably, ALF outcomes improved over time, in association with increased survival without transplantation. We speculate this improvement is possibly related to better selection of candidates, a reduction in days from transplantation listing to actual transplantation during the later period as well as improved supportive care. Future studies should focus on more accurate prognostic markers of liver regeneration and on optimizing early transplantation availability in order to prolong survival in these patients.AbbreviationsALF

acute liver failure