INTERNATIONAL LIVER TRANSPLANT SOCIETY
Recent decades have witnessed a progressive change in the incidence of different aetiologies of Acute Liver Failure (ALF) in the East and West; however, no nationally or internationally consolidated analyses are available.
Since the introduction of antiviral therapies and vaccines in the 1990s, Europe and the United States have seen a decrease in the number of cases of ALF with viral etiology and a relative increase in the number of cases of acetaminophen-induced ALF. In Europe, the etiology with the highest incidence is idiopathic (2004-2009 estimate: 33%). Over the past decade, the United States has seen a decrease of more than 50% in ALF-related liver transplant waiting list registrations.
In the US and Eurotransplant countries, the mortality rate of patients with ALF on the transplant waiting list is approximately 20% and 15%, respectively.
In Europe, one-year patient and graft survival after liver transplantation for ALF is 74% and 63%. To date, no prognostic factors for transplant success are universally accepted by the scientific community.
Objectives
The International Acute Liver Failure Registry aims to
measure the true practice of ALF worldwide and its associated outcomes by recruiting multiple international centers committed to consecutive submission of patient data while undergoing rigorous data validation. The primary endpoint of this study is 90-day and 1-year morbidity and mortality for both recipient. Secondary endpoints include the identification of modifiable predictors of outcome. Additional outcome data, including complication and rescue rates, will be captured at 12 months follow up. It is hoped that these data will provide a more appropriate guide for healthcare practitioners and patients to assess the true global outcomes in ALF without the impact of center bias, allowing to identify predictors and respective preventive measures to optimize perioperative care and outcomes in ALF worldwide.
Methods
Study design
The proposed international collaborative prospective patient registry follows an observational cohort study design, allowing to gain a cross-sectional insight into the worldwide practice of ALF treatment and related outcomes on morbidity and mortality. Patient registries are powerful tools to observe the course of the disease, understand variations in treatment and outcomes, examine factors that influence prognosis, describe care patterns, assess effectiveness, monitor safety and harm, and measure the quality of care and costs.
Participants
There is no minimum threshold on the quantity of cases. All healthcare practitioners across the world involved in ALF treatment are eligible to participate, including surgeons, anesthesiologists, hepatologists, critical care physicians and other members involved in ALF treatments. Auditors (data monitors) will be assigned to verify the adherence to the registry protocol and audit the quality of data collection of the participating centers.
Eligibility criteria
Data from all patients with ALF are eligible for inclusion into the registry. The inclusion criteria involve both adult and pediatric patients with ALF.
Each patient requires a minimum 90-day follow-up period and both the
for the follow up period to complete a valid submission to the registry. Additional outcome data will be captured at 12 months follow up. All patients must be registered prospectively.
Variables, data sources, and measurements
The collected variables are listed in the CRF.
The Case Report Form (CRF) contains all the variables and their definitions, available at https://ALFregistry.org/CRF. The electronic CRF is designed to mandate data entry for certain fields (e.g., morbidity, mortality, etc.) and has set maximum and minimum values for each to reduce errors in data caption and enhance the quality of data collection. Discrete variables are recorded using dropdown selections for ease of use. Where relevant, descriptions of key data fields are provided. To convert between units and thus ensure uniformity of data collection, definitions and information concerning scores/classifications and specific calculators are provided at ALFregistry.org.
Study size
The study aims for the maximum number of patients to recruit. The first report of initial registry outcomes will be published once the number of valid cases submitted to the registry reaches 200 or more.
Statistical methods
The PI and Founder Team of the Registry will perform descriptive and exploratory statistics.
Continuous variables will be compared with the student t-test, the Mann-Whitney U test and the Kruskal-Wallis H test or one-way ANOVA as appropriate. Differences among proportions derived from categorical data will be compared using the Fisher or the Pearson chi-square tests as appropriate. Univariable and multivariable logistic and cox regression models will be used to identify factors independently associated with outcomes and to adjust for confounding. The results of the multivariable analyses will be reported as adjusted odds ratios (OR) and hazard ratios (HR) with 95% confidence intervals. ROC curves and the Youden's index will be used to identify optimal cut-off points for continuous variables. All p-values will be 2-sided and considered statistically significant if p <0.05 in the univariate analysis and p <0.10 in the
multivariate analysis. Missing data from not mandatory to submission fields will be clearly reported. Cases with incomplete data regarding morbidity or mortality will be excluded from the analysis, and the number of those will be reported. Statistical analysis will be performed using R version 3.3.2 (R Core Team, GNU GPL v2 License), R Studio version 1.0.44 (RStudio, Inc. GNU Affero General Public License v3, Boston, MA, 2016) with the graphical user interface (GUI) rBiostatistics.com (rBiostatistics.com, London, UK, 2017).
Discussion
At present, many published ALF cohorts originate from high-volume centers in Western countries (13-16). However, the actual global morbidity and mortality, particularly from high-volume centers in Eastern countries, remain unknown.
The significant heterogeneity of the cohorts and etiologic suggests a significant difference in outcome. It highlights the urgent need for a prospective registry to identify modifiable predictors of outcomes for patients with ALF. The underreporting of patients with ALF compounds the need. Data from the most crowded population, India and China, are lacking. The question remains if LDLT, as it is done mainly in the east part of the world, is better than in the west.
Long-term outcomes following living donor liver transplantation (LDLT) and deceased donor liver transplantation (DDLT) were similar in adult patients with acute liver failure (ALF) (17, 18). However, the main obstacle is the period for patients with ALF. The earlier the transplant, the better the patient’s outcome.
The time to transplantation is a critical factor influencing overall outcomes. In a US study (16), the median time to transplantation was 3.0 days, significantly longer than the 1-2 days reported in the United Kingdom for ALF patients overall. A French study demonstrated even shorter times, with a median time from listing to transplantation of just 16 hours, and 89% of patients transplanted within 48 hours. Notably, one UK study reported that 76% of listed patients underwent liver transplantation, likely reflecting faster organ availability . For ALF, living donor liver transplantation (LDLT) has the potential to significantly reduce the time to transplantation, which could improve patient outcomes by mitigating the progression of liver failure and associated complications. However, large-scale data to support this advantage is currently lacking. Establishing a comprehensive registry could address this gap by systematically collecting and analyzing data, enabling better evaluation of LDLT's impact on time to transplant and long-term outcomes in ALF patients.
In conclusion, many published acute liver failure (ALF) studies are from Western high-volume centers, with limited data from Eastern countries, despite their large populations and potential differences in outcomes. The heterogeneity in etiologies and outcomes underscores the urgent need for a global prospective registry to identify modifiable predictors of ALF outcomes. Living donor liver transplantation (LDLT), more common in Eastern countries, may shorten the time to transplantation and improve outcomes, but comprehensive data is lacking. Establishing a registry could provide insights into the comparative effectiveness of LDLT versus deceased donor liver transplantation (DDLT) and address underreported ALF cases worldwide.
Funding: No funding
Platform
The ALFregistry.org platform is built on Drupal version 9, an open-source content management system written in PHP and distributed under the GNU General Public License. Two Apache servers (one used as a backup) physically based in the United States of America with a MySQL database are used. The most advanced firewalls are installed for monitoring and prevention of malware. The website and software compatibility for different platforms, internet browsers, and devices were assessed using BrowserStack.com. The platform is “self-maintained” with automated updates.
Monitoring The Management Committee is responsible for monitoring the CRF export database monthly. All participating centers will undergo regular onsite peer monitoring. Auditors (data monitors) from non-surgical disciplines will be assigned to ensure protocol adherence and to audit the quality of data collected at each center.
Safety
This study presents no physical risk to patients or researchers. Data confidentiality is ensured through local anonymization. Anonymization will be monitored, and any breaches will be reported. Individual participants will be accountable to their local authorities in the case of confidentiality breaches.
Research ethics approval
Actually, not done
A single analysis without hierarchical authorship (no first author, no last author) is planned for the first report (a “pure” group author publication) to reflect the collaborative effort of the project. All project participants are encouraged to step forward with suggested secondary analyses on specific questions and will be granted full access to the acquired data once the ALFregistry.org Committees approve their proposal.