Evolution of Indications for Liver Transplantation (LTx) in the Years 2001–2017 in Poland

Background

During the last 5 decades, transplants have become the standard and often the only method of treatment for many patients. In the case of liver transplantations, the main causes are chronic HBV and/or HCV infections and their cause, HCC. These viruses have been classified by the International Agency for Research on Cancer (IARC) as undoubtedly carcinogenic to humans (group 1) [1].

The World Health Organization (WHO) estimates that about 500 million people worldwide are infected with HBV or HCV. Moreover, in the WHO European Region, about 13.3 million people currently live with chronic hepatitis B (about 1.8% of all adults) and 15 million have chronic hepatitis C infection (about 2% of the adult population). According to data from the European Center for Disease Prevention and Control (ECDC), in the European Union countries, the overall hepatitis B incidence is 1.49/100,000 and 8.7/100,000 for hepatitis C. The very high incidence of infections among people who inject drugs is especially concerning [2]. Geographically, the great majority of HBV infections are in the WHO African and Western Pacific Region, whereas for HCV infections the regions with the highest prevalence are the WHO European Region and the WHO Eastern Mediterranean Region [3].

In Poland, there are approximately 130,000 people currently infected with the HCV virus and 300,000 with HBV infection [4,5].

According to the National Cancer Registry data, the number of HCC cases in the years 2001–2016 was growing. Most importantly, among all liver cancer types, HCC is the most characteristic for people about 50 years old, as risk of the disease grows with age (Figure 1).

Material and Methods

LIMITATIONS OF THE STUDY:

Some of the obtained data are estimates. Some of the changes found could have resulted from improved reporting. Data on the occurrence of hepatitis B and C may have been underestimated due to the large number of undiagnosed cases.

Results

The analysis of the received data suggests that HBV and HCV infections, as well as HCC, are among the most frequent indications for primary liver transplantations in Poland in the years 2001–2017. In the analyzed period, overall, about 44% (1456) of LTx cases were combined with HBV and/or HCV and/or HCC. In this group, transplants performed in patients who only had 1 specific factor – HCV – were also a large cohort (about 40%) (581). Transplants performed in patients who only had HBV and in those who only had HCC accounted for 12% (185) and 5% (69), respectively. In the analyzed group, another relatively large cohort (18%) was transplant cases who had both HCV and HCC (266). Within the analyzed period, this group also showed the most significant increase in the number of cases – from 0 in 2001 and 2002 to 32 in 2017 (and 48 cases in 2014).

The lowest number of primary liver transplantations was performed among patients who had HBV and HCV infections and other diseases at the same time (but not HCC) – about 1% (14). Other rare indications for primary liver transplantation were HCV, HBV and HCC with other diseases (about 3%) (42), and HCC with other diseases but not with HCV and HBV (about 3%) (42) (Table 1).

As the strongest factors leading to the need for LTx were HCC, HBV, and HCV, we also decided to analyze epidemiological data on incidence of these factors for a similar period in Poland. In accordance to the analyzed data on HCC and hepatitis B and C in Poland in the years 2001–2017 (without data from 2017 for HCC), an increasing incidence trend was observed. The number of cases of all liver cancer types in Poland in the years 2001–2016 was similar and represents a stable trend, but after isolation of the HCC cases, an increasing trend of the number of these cancers is visible (Figure 2).

Over this period, the percentage of HCC cases among all liver cancer types increased significantly. In 2001, only 17% (274) of all liver cancer cases were diagnosed as having HCC, but at the end of the analyzed period in 2015 and 2016 it was 50% (766) and 48% (705), respectively (Table 2), which is also reflected in LTx demand.

Similar to the data on HCC, epidemiological data on hepatitis B and C indicates the growth of the number of cases in the years 2001–2017 (Figure 3). A significant increase in hepatitis B and C cases was observed in 2014. In comparison with 2013, in 2014 there were 1222 more hepatitis B cases, which means that the incidence per 100,000 population had increased from 4 to 7.18 and became even higher in the following years. Likewise, in the case of hepatitis C, there was growth of about 845 cases and the incidence per 100,000 increased from 7.03 in 2013 to 9.23 in 2014, and was even higher in the following years. The small decrease in the number of cases in 2017 is a probable artefact that will be corrected when data is updated, as it was in previous years (Figure 3, Table 3).

The obtained data also proved that hepatitis C was much more common than hepatitis B and HCC in the Polish population for most of the analyzed period, which also is associated with LTx demand. This was observed since 2003, when a trend reversal took place. In the years 2001 and 2002, the number of hepatitis B cases was higher than hepatitis C cases, by about 441 and 43 cases, respectively (Figure 3, Table 3).

Discussion

The obtained data suggest that one of the most frequent indications for primary liver transplantations in Poland in the years 2001–2017 was the combination of HBV, HCV, and HCC infections in various combinations (joint and separate occurrence) (Table 1). A similar conclusion was reached by Crespo et al., who found that hepatitis B and C viruses, as well as HCC, were the most typical indications for liver transplantations [10]. Moreover, Farkas et al. argue that for patients with complications such as HCC, liver transplantation is the only treatment option [11].

In the analyzed group, the highest number of LTx was performed among patients who demonstrated persistent HCV infections with or without HCC. Graziadei et al. also state that in many European and American countries, chronic HCV infection is the leading or second indication for liver transplantation [12]. The obtained results also suggest the smaller role played by HBV on LTx demand. The reason behind this phenomenon can be found in the introduction of the vaccine against hepatitis B into the vaccination program in 1989. At the beginning of the 1990s, a decrease in hepatitis B occurrence was observed due to the introduction of the program for the prevention and eradication of hepatitis B. Additionally, across the country, screening of blood and organ donors and enhanced protection in hospitals were introduced. Kowalska et al., however, found that in recent years in Poland there is has been a clear plateau trend in hepatitis B cases, and the disease is now more often detected, especially among young adults (older than 35 years) who have not been vaccinated as part of the vaccination program [13]. In 2015, Poland introduced direct-acting antiviral treatment (DAA), which is characterised by very high effectiveness, better tolerance than interferon treatment, and shorter time of admission (12 weeks) [14]. Non-interferon treatment is reimbursed by the National Health Fund as part of the therapeutic drug program led by the Ministry of Health in Poland [15]. However, the obtained data do not reflect this important achievement. A possible explanation is the short time since the program’s introduction, as well as the high percentage of people who are not aware of their infection. The most recent reports estimate that there are about 150,000 people (about 0.5–1% of the population) in Poland with chronic HCV infection, 80% of whom are not aware of this fact [4,16,17].

The obtained data on HCC show that this type of liver cancer in the analyzed period was becoming more frequent, and its effect on liver transplantation demand could become more visible in the future. Flisiak et al. presented 3 scenarios on the development of HCV incidence in Poland until 2030. One of the scenarios assumes a significant increase (60%) in HCC incidence related to HCV (1250 cases) until 2030 [18]. Taking into consideration the presence of other strong risk factors that play key roles in cancer development in general and specifically in HCC, we can assume that primary liver transplantations caused by HCC will become more frequent due to factors such as the aging of Polish society and increased alcohol intake. The vast majority of liver cancer cases occur among people aged 55 years and older (about 82% among men and 88% among women). The risk of this disease increases with age and is the highest in the ninth decade of life for both sexes [19]. Moreover, the State Agency for the Prevention of Alcohol-Related Problems in Poland reported an increasing trend in alcohol consumption. In 2017, each citizen on average drank 3.3 litres of alcohol. In comparison, in 2007 and 1997 this was 3.0 and 2.8 litres per person, respectively [20].

To date, there is no national program targeting the eradication and prevention of HCV infections in Poland. Moreover, coordinated HCV screening is still unavailable at the level of primary healthcare. In 2013, National Health Fund expenditures for HCC treatment and liver transplantations was 16.8 and 17.8 million PLN, respectively. These were only direct costs incurred by the taxpayer and are probably significantly underestimated [21].

Hepatitis B and C are the main causes of HCC worldwide and are responsible for about 77% of cases of this type of cancer [22]. These 3 main reasons for primary liver transplantations are caused by these 2 viruses, which are completely modifiable risk factors. The introduction of effective primary prevention solutions, as well as improvement of the currently existing ones, would be beneficial both for patient health and for the budget of the National Health Fund. An example of spectacular results delivered by reducing exposure to modifiable risk factors is the decline in the incidence and mortality rates of stomach cancer in Poland. Among others measures, the introduction of effective antibiotic therapy prompted an almost 3-fold decrease in stomach cancer cases during the last 4 decades [23]. Another good example showing the effect of the elimination of infectious factors leading to severe health consequences comes from Australia. Since 2007, Australia has run a vaccination program for HPV eradication (for girls and boys), which is expected ultimately to eliminate HPV in the next 2–3 decades in that country [24].