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Liver Transplantation in Croatia: “David Among Goliaths”

Mrzljak, Anna MD, PhD, FEBGH1,2; Mikulic, Danko MD, PhD, FEBS3; Busic, Mirela MD4; Vukovic, Jurica MD, PhD2,5; Jadrijevic, Stipislav MD, PhD3; Kocman, Branislav MD3

Author Information
doi: 10.1097/TP.0000000000003453
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INTRODUCTION

Croatia is a European Union (EU) member state, geographically located in south-east Europe, bordering Slovenia, Hungary, Serbia, Bosnia and Herzegovina, Montenegro, and sharing a maritime border with Italy (Figure 1). Croatia has a population of 4.1 million, with a median age of 43.1 years. The average life expectancy at birth in 2017 was 78.2 years, 3 years lower than the EU average.1 The estimated gross domestic product (GDP) per capita/y in 2018 was US $14 815.9.2 Croatia spends 6.8% of its GDP on health. The healthcare service is mostly public, and the mandatory health insurance system is complemented by voluntary insurance.1 The country’s healthcare coverage is universal, covering most medical treatments, including transplantation.

FIGURE 1.
FIGURE 1.:
Map of Europe. Croatia (red) is located in southeast Europe, surrounded by Slovenia (Slo), Hungary (H), Serbia (S), Bosnia and Herzegovina (BiH), Montenegro (M), and sharing a maritime border with Italy (I). Croatia has been a member of Eurotransplant since 2007. Other Eurotransplant member states are presented in dark blue; the Netherlands (N), Belgium (B), Luxemburg (L), Germany (G), Austria (A), Hungary (H), and Slovenia (Slo). The map from Figure 1 has been purchased from the Stock Adobe https://stock.adobe.com.

Liver Transplantation in Croatia

The rapid evolution of the Croatian liver transplantation (LT) program over the last decade has been directly linked to growing deceased donor rates3 (Figure 2). Croatia has one of the highest LT rates worldwide (23–33 per million population) and has a median waiting time for LT of less than a month.3,4 This achievement is mainly due to the multidisciplinary approach and the leadership at the transplant center level along with the effective management of the deceased donation in the country and in donor hospitals.

FIGURE 2.
FIGURE 2.:
Actual deceased donor rate (blue) and liver transplant deceased rate (red) per million population in Croatia for the period 2010–2019.3

History

The Croatian LT program has a 30-year history. The first LT was performed in 1990 at the University Hospital Centre Zagreb (UHCZ). However, during the Croatian War of Independence (1991–1995), all LT activities were on hold. The LT program at the Merkur University Hospital (MUH) was launched in 1998. LT in Croatia is currently performed at both institutions with the vast majority (90%) at MUH.5 The program started under challenging circumstances, burdened with the lack of donors and funding but has gradually grown based on enthusiasm of transplant professionals supported by a national transplant organization. Since 1998, over 1500 LTs have been performed at MUH, and the adult LT program has been gradually complemented with living donor, split liver, and multi-organ transplants such as liver–kidney and liver–pancreas. Today, MUH runs one of the busiest LT programs within the Eurotransplant area, as shown by its high volume activity (113 LTs performed in 2019)4 and provides educational efforts for countries in the region with low or nonexisting LT programs. The pediatric LT program was launched in 2001 at UHCZ, offering living donor, split and deceased donor transplants. The main challenge in a country of Croatia’s size is a low volume of pediatric cases with end-stage liver disease.

Eurotransplant and Liver Allocation

Eurotransplant is an international nonprofit organization responsible for organ allocation and cross-border sharing among 8 EU member states (Figure 1).4 Croatia joined ET in 2007, 6 years before joining the EU. For a small country like Croatia, ET membership has helped tremendously in facilitating liver allocation, especially for the country’s most critical patients. Croatia applies Model for End-Stage Liver Disease (MELD)-based liver allocation system. In addition, improved access to LT is promoted in cases where the severity of the patient’s disease is not accurately reflected by MELD scores through the system of “standard exceptions” (SE). Patients with SE status are granted a specific initial value of MELD points reassessed at 90-day intervals.6 The list of SE indications is defined nationally, whereas most SEs in Croatia are granted for hepatocellular carcinoma (HCC). An expert national audit group also grants a “nonstandard exception” status to any patient outside predefined prioritization criteria.

Deceased donor livers for elective patients are primarily offered nationally and then to other ET member states according to specific allocation rules.6 Patients granted a high urgency (HU) status (eg, acute liver failure or early graft failure) are given priority at the international ET level and the allocation policy works towards providing livers for these recipients within a 48-hour time frame.7 The liver exchange balance within the ET is accomplished through the “payback” policy, where an obligation to return a liver is created for every imported HU organ. In addition, implementation of ETs allocation policy based on transparent medical criteria has contributed to the preservation of public trust in a “fair” organ allocation process.

Donor Pool and Liver Utilization Rate

As in most Western countries, deceased donor LT constitutes the majority of LTs in Croatia. So far, most recipients (98%) received whole deceased donor liver grafts from brain dead donors with few (2%) recipients receiving partial grafts from brain dead or living donors.4 In 2019, the utilization rate of deceased donors in Croatia had been 98% with the majority (92%) transplanted in the country.4

Utilization of extended criteria organs, especially the use of elderly livers has been one of the key strategies in the growth of Croatia’s LT program. Currently, the median age of deceased donor livers is 61 years, compared with a median of 54 years in ET.4 The acceptance of steatotic livers and livers from anti-HBc positive donors is an additional strategy in expanding the liver donor pool and increasing liver utilization rates.

INDICATIONS AND OUTCOMES

Cirrhosis is the main indication (64%) for LT in all adult age groups, with alcoholic liver disease being the leading etiology (62%) followed by virus-related cirrhosis (15%).8 Malignancies represent 26% of overall indications, mainly HCC (81%) with an increasing trend over the past several years.8 Hilar cholangiocarcinoma in selected patients after neoadjuvant radiotherapy is the most frequent indication for non-HCC oncologic indications (75%), followed by metastatic neuroendocrine tumors (19%).8

HU transplants represent 5.4% of LT procedures; 9.8% are retransplants.4 During the last decade, liver retransplants (re-LT) have shown a shift in indications with an increasing proportion of late re-LTs. Biliary pathology and recurrent diseases are the predominant indications, and the improved access to re-LTs has been generated primarily by the increased availability of donors.9

Since the launch of the pediatric program, 50 children (4 mo–16 y) underwent 57 LTs [segmental grafts from living donors (33%), segmental (49%), and whole (18%) grafts from deceased donors]; biliary atresia has been the leading indication (35%).

Outcomes

The Eurotransplant Liver Registry (ELTR) collects data from 33 countries and 174 institutions and includes >95% of European LT data.8 In Croatia, 1-year and 5-year adult patient survival rates are 83% and 70%, respectively, which is slightly lower than the ELTR data of 86% and 74%.8 Pediatric 5-year and 10-year survival rates are 64.5% and 61.1%, suggesting room for improvement.

CHALLENGES AND PERSPECTIVES

Our transplant activities have been recently challenged by coronavirus pandemic that has affected healthcare systems globally. In Croatia, the first coronavirus disease 2019 (COVID-19) case was confirmed on February 25, 2020, which subsequently led to temporary hold of transplant programs, with the exception of high priority liver candidates. Transplant activities reopened at the beginning of May 2020 and continued without disruption, incorporating additional molecular severe acute respiratory syndrome coronavirus-2 testing of donor and recipient before the procedure.

In conclusion, Croatia has come a long way during the past 3 decades – from having an almost nonexistent LT program to being one of the leading countries when it comes to LT availability. However, much work remains to be done. The development of a national transplant registry, further expansion of the donor pool with strategies focused on living donation and donation after circulatory death, the introduction of novel technologies including machine perfusion, and finally, activities promoting access to LT in bordering countries with low volume or nonexisting transplant programs will be tackled moving forward.

REFERENCES

1. OECD iLibrary Croatia: Country Health Profile 2019, State of Health in the EU. Available at https://www.oecd-ilibrary.org/social-issues-migration-health/croatia-country-health-profile-2019_b63e8c9f-en. Accessed August 18, 2020
2. Global Finance. Croatia GDP and Economic Data. Available at https://www.gfmag.com/global-data/country-data/croatia-gdp-country-report. Accessed August 18, 2020
3. IRODAT. International Registry in Organ Donation and Transplantation. Available at https://www.irodat.org/. Accessed 13 August 13, 2020
4. Eurotransplant. Available at https://www.eurotransplant.org/. Accessed August 13, 2020
5. Croatia Ministry of Health. Godišnja izvješća. Available at https://zdravlje.gov.hr/programi-i-projekti/nacionalni-programi-projekti-i-strategije/nacionalni-transplantacijski-program/godisnja-izvjesca/1605. Accessed August 13, 2020
6. Eurotransplant. Liver Allocation System. Chapter 5. Available at https://my.eurotransplant.org/wp-content/uploads/2020/07/H5-ELAS-MELD-Nov-2019.pdf. Accessed August 13, 2020
7. Jochmans I, van Rosmalen M, Pirenne J, et al. Adult liver allocation in Eurotransplant. Transplantation. 2017; 101:1542–1550
8. European Liver Transplantation Registry. Available at http://www.eltr.eu/. Accessed August 14, 2020
9. Mrzljak A, Skrtic A, Mikulic D, et al. Liver re-transplantation in Croatia: change in graft histopathology [published online ahead of print, 2020 Jul 15]. Transpl Int. 2020. doi:10.1111/tri.13701
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