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Liver transplantation for autoimmune liver disease –Twelve-year trend analysis in a mixed ethnicity country
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Introduction
Autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) and primary biliary sclerosis (PSC) represent three major etiologies of chronic and progressive autoimmune liver disease[1]. The evolution of AIH and PBC towards end-stage liver disease has been modified with the availability of effective therapy. Since the 1970s, treatment of AIH with corticosteroids has proven to be successful in preventing cirrhosis and the need for liver transplantation in the majority of patients[2]. Similarly, since the 1990s, ursodeoxycholic acid (UDCA) therapy has achieved in slowing PBC progression to end-stage liver disease in approximately two-thirds of treated patients. Unfortunately, effective medical therapy for PSC is yet to be discovered[3,4].  
The need for liver transplantation is a useful surrogate to estimate the burden of autoimmune liver diseases and the impact of current treatments. In US and European surveys, autoimmune hepatitis represents the 5th -7th cause of acute liver failure [5–8]. When analyzing liver transplantation indication for end-stage liver disease, listing for PBC decreased 50% in the last 20 years; whereas HAI remained infrequent (~3% throughout the study period) and PSC became the main indication for autoimmune liver disease transplantation in United States and United Kingdom since 2014[9]. Similar observations have been made in other European countries[3,10].
Most  of these trends were described in regions where a significant proportion of the population is caucasian–over 70% of analyzed patients[9]. In Argentina, a country with mixed-ethnicity[11], the prevalence of autoimmune liver disease is quite different: AIH was the second etiology of acute liver failure and the fourth etiology of liver transplantation for end-stage liver disease in published reports [12,13]. Regarding cholestatic liver disease, PBC represented the 5th and PSC the 9th indication for non-emergency liver transplantion.
Thus, we aimed to describe waiting list registration and liver transplantation trends for autoimmune liver disease in Argentina, in order to determine if changes in tendencies match with those observed in countries with a different ethnical background.
Patients and Methods:
Database
We designed a population-based, time-series analysis of patients registered in the SINTRA database between January 1st, 2005 and December 31st, 2017. SINTRA is the Argentinian database of the National Procurement Organization (INCUCAI), in which all liver transplant activity is recorded, including: information regarding donors, waiting list candidates, and transplant recipients. We accessed and collected publicly available data through the sintra.incucai.gov.ar web page on ………., 2018.
Definitions and inclusion/exclusion criteria
We included all adult patients (>18 years old) who were registered on the waiting list for liver transplantation or received a liver transplant in the above mentioned period in Argentina with a primary indication of autoimmune liver disease: AIH, PBC or PSC. Etiologic data was obtained from SINTRA diagnostic codes; in which only one possible diagnosis was considered (there is no dual diagnoses registry allowed). Both patients listed in the emergency status for acute liver failure/fulminant hepatitis as well as those listed for end-stage liver disease were considered and analyzed separately.
Patients were excluded if they were listed with indications other than AIH, PBC or PSC, if they received a combined transplant, if they previously received a liver transplant or in case or living donor liver transplantation.
Cumulative incidence rates were calculated for each 12 month period between 2005 and 2017, starting the first day of January and ending the last day of December of the following year. The denominator was the adult Argentinian population (data was extracted from age stratified population´s annual estimations of the National Institute of Statistics and Censuses Institute).  Waiting list registration rates were calculated every 1.000.000 persons for each 12 month period.
Patients were stratified by age at the time they were listed, as follows: 18-24 years old, 25-29 years old, 30-39 years old, 40-49 years old, 50-59 years old, 60-69 years old and patients older than 70 years. Patients were considered to have hepatocellular carcinoma (HCC) when exception MELD points for HCC were approved. In SINTRA registry, HCC is not specifically recorded in the waiting list registration process –an individual code for this diagnosis is not provided--. Data are only available in transplant recipients if exception points were given for HCC within Milan criteria. SINTRA does allow for discrimination of whether exception points were given for HCC or for other reasons. If MELD exception points for HCC were approved, patients were listed with 22 points -- plus 1 point every 3 months on the waiting list-- until transplantation. It is estimated that HCC MELD exception point’s approval rates reach 66% in Argentina.
Joinpoint regression analysis
Cumulative incidence rates were age and sex-adjusted considering both the WHO and US 2000 standard population. Trends were estimated by joinpoint regression analysis considering age and sex-adjusted rates by the US 2000 population. We used joinpoint analysis to identify years were changes occurred in the linear slope of the temporal trends. In the analysis of yearly rates throughout the 10-year period study, whenever a significant change in its trends was detected, the best fitting point was identified and referred to as “a joinpoint”.  This model not only allows identifying significant changes in trends during a specific time period (January 2005- December 2017) but also estimates the magnitude of increase or decrease seen in each interval by estimating the annual percentage change (APC), with its corresponding 95% confidence interval and statistical significance14. The terms increase or decrease were used when the slope presented with an APC different than 0.5% and a p-value <0.05; otherwise trends were considered stable or level. The JoinPoint Regression Program 4.4.0.0 software developed by the United States National Cancer Institute was used15.
 
 
References
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