Analysis of clinical-biological markers and scoring of patients with liver cirrhosis in the liver transplant program: Summary of doctoral thesis in medical sciences: 321.24 – Transplantology

Abstract

Actuality and importance of the researched problem: Although recent years have seen a steady increase in the incidence of liver disease, which is a serious problem in modern medicine, viral liver cirrhosis is still certainly underestimated both nationally and globally. Currently, worldwide 844 million people are registered with chronic liver disease, with a mortality rate of 2 million deaths per year, including 1 million deaths due to complications of cirrhosis and 1 million due to viral hepatitis and hepatocellular carcinoma [1]. Liver disease is becoming more and more common lately and more alarming worldwide, as well as in the Republic of Moldova, 75% of deaths caused by pathology of the digestive system are due to liver cirrhosis [2]. Epidemiological analysis of viral liver cirrhosis showed a 3-fold increase in morbidity in 2019 compared to 2000. As a result of which, the number of patients with liver cirrhosis of viral etiology increased in 2019 to 5482 patients. Also, in the case of chronic viral hepatitis, the majority of patients were detected with hepatitis B virus. In the multi-year dynamics the prevalence index of HBV morbidity increased from 655 cases (15.3 cases per 100 thousand inhabitants) in 2000 to 2422 cases (68.32 cases per 100 thousand inhabitants) in 2019. The prevalence rate in liver cirrhosis caused by C virus increased practically 9-fold, from 229 cases (5.4 cases per 100 thousand inhabitants) in 2000 to 2240 cases (63.19 cases per 100 thousand inhabitants) in 2019. Viral liver cyonoses, other etiologies and those not specified, showed a slight decrease from 522 cases (12.2 cases per 100 thousand inhabitants) in 2000 to 420 cases (11.85 cases per 100 thousand inhabitants) in 2019 [3]. Thus, at this stage, viral liver cirrhosis and primary liver cancer represent one of the most serious problems for the population, due to their global spread, increased morbidity and mortality, and the high degree of disability caused by the rapid progression of these pathologies. Globally, approximately 257 million people are infected with chronic viral hepatitis B, while 71 million people are infected with chronic viral hepatitis C, mainly in less developed countries. In 2019, 10 thousand patients with liver cirrhosis were registered in the Republic of Moldova, as a result of which 70% of patients with cirrhosis developed primary liver cancer. Morbidity for viral etiology liver cirrhosis, caused by virus D, increased from 183 cases (4.3 cases per 100 thousand inhabitants) in 2000 to 400 cases (11.28 cases per 100 thousand inhabitants) in 2019. What denotes a higher prevalence for the Republic of Moldova is HDV viral liver cirrhosis, which has a more aggressive and rapid evolution compared to other viral liver cirrhosis [3]. Over the past two decades, efforts have focused on reducing mortality on the liver transplant waiting list without compromising post-transplant outcomes. However, it can be 5 difficult to identify candidates who are too ill for HT to prevent unnecessary transplants [39]. The implementation of the MELD score was the first and most important change in liver allocation, redirecting donor organs to the sickest patients and aiming to reduce waiting list mortality [4]. Notwithstanding the fact, that there is a need for continuous consolidation and development of new prognostic scores for the end-stage liver disease population on the waiting list for liver transplantation in the Republic of Moldova, the validation of new scores and in fact what defines the research problem at hand, which is predestined to improve and prolong the quality of life of patients on the waiting list within the national liver transplantation system. Thus, based on the above, the aim of the scientific work is to: study the clinical-biological landmarks and analyze different prognostic scores on the population with viral liver cirrhosis from the waiting list for liver transplantation in the Republic of Moldova. The following general research objectives were stipulated to achieve the aim: 1. Evaluation of clinical-biological landmarks in patients on the waiting list for liver transplantation 2. Analysis of prioritization factors of recipients for liver transplant waiting list 3. Comparison of predictive accuracy between MELD score, MELD Na, MESO-index on mortality in the first 3 months after liver transplant listing 4. Validation of the MELD 3.0 prognostic score for mortality in the first 3 months of recipients on the liver transplant waiting list 5. Development of the algorithm for enrolling patients with decompensated viral liver cirrhosis on the liver transplant waiting list based on the validated maximum predictive accuracy prognostic score Scientific research methodology The present work represents a stepwise, retrospective and analytical clinical study focused on the evaluation of clinical parameters, results of instrumental methods of diagnosis and monitoring of 265 patients with viral liver cirrhosis included in the waiting list for liver transplantation. With the application of prognostic scores to predict mortality rate in the first 90 days after listing for liver transplantation. Statistical analysis was performed using SPSS software, version 23.0. Data are reported as mean±SD. Gaussian normal distribution was tested by applying normality tests (ShapirkoWilk test); and homogeneity of variance was checked by Levene's test. Differences between groups were detected by performing the independent t-test for normally distributed homogeneous values and the Welch test for non-homogeneous normally distributed values. The Mann-Whitney 6 U test was applied for non-parametric data or for parametric data not following the normal distribution. Differences were considered significant at a p-value less than 0.05. The PhD scientific project was favourably approved by the Research Ethics Committee of the IP USMF "Nicolae Testemitanu" (no. 47 of 17.06.2019). Novelty and scientific originality of the results obtained: Taking into account the increasing number of patients on the waiting list with viral liver cirrhosis, the long waiting time, the rapid progression of the disease with increased mortality rate of patients, for the first time an interdisciplinary clinical and paraclinical study was conducted, with a complex evaluation of prognostic scores predicting mortality in the first 90 days of listing, with the creation of a monitoring system validated and adapted for the Republic of Moldova. Careful monitoring and re-evaluation of candidates at regular intervals has been implemented which can improve the success of the liver transplant programme and the overall patient outcome. Scientific and practical problem solved The scientific-practical problem solved in the research is the development of the rational algorithm for evaluation and triage of patients with liver cirrhosis of viral aetiology from the waiting list in various clinical situations and greater accessibility in the view of the liver transplant coordinator team. Theoretical importance and applicative value of the study The applicative value of the study is reflected in the scientific work - the analysis of the concepts of scientists in the country and abroad, the hypotheses and problematizations made, as well as the knowledge we have gained through our PhD research, will broaden the horizon of research of clinical-paraclinical features in patients with liver cirrhosis of viral etiology and the assessment of prognostic scores of short-term mortality risk for patients included in the waiting list for liver transplantation. New scores have been proposed that exceed the predictive value of the MELD score and would facilitate the inclusion of patients on the liver transplant waiting list depending on the severity of the disease, so that patients with end-stage liver disease in severe disease are given priority for liver transplantation. Also in teaching activity - the conclusions and recommendations presented in the paper can be used in the training process of students/residents; practical activity - the acquired knowledge and the proposed recommendations will improve the work of clinics. Implementation of research results. The practical impact of the present study is the external validation of the new MELD 3.0 score on the population with viral liver cirrhosis from the waiting list for liver transplantation in the Scientific Surgical Laboratory ,,Reconstructive Surgery of the Digestive Tract'' Nicolae 7 Testemitanu State University of Medicine and Pharmacy, Chisinau, Republic of Moldova. In addition, the results obtained (validation of the new prognostic mortality score in the first 90 days after listing) were presented to medical students during the classes at the Department of Surgery No. 2. Approval of scientific results. The results obtained were discussed and presented at the following scientific forums: the National Congress of Surgery, Sinaia, 2022, the National Congress of the Romtransplant Association, edition 2022, the scientific-practical conference with international participation ,,Hepatobiliary-pancreatic surgery, abdominal parietal defects, advanced laparoscopic surgery'', Chisinau, 2022, the annual scientific conference ,,Research in biomedicine and health: Quality, Excellence and Performance'' dedicated to the 77th anniversary of the founding of Alma Mater. National Conference ,,Days of the CF Clinical Hospital Iasi'', edition 2022, Scientific Conference with international participation dedicated to the Medical Days of the Municipal Clinical Hospital ,,Saint Archangel Michael'' 1st edition, 21.11.2022, International Scientific Conference ,,Tissue and Cell Transplantation. Actualități și perspective'', National Scientific Conference on BPH Surgery, 20.04.2023 - 23.04.2023, Bucharest, Congress Balkan Medical Week, XXXVII edition Perspectives of Balkan Medicine in the post COVID-19 era, 7-9 June 2023, Chisinau, Republic of Moldova, National Congress of Surgery. The XIVth Congress of the Association of Surgeons ,,Nicolae Anestiadi'' of the Republic of Moldova. 21-23 September 2023. Publications on the research topic. 29 scientific papers have been published on the subject of the thesis, of which: 10 articles in scientific journals, 9 theses, 1 abstract in SCOPUS journal. 1 patent, active participations in national and international scientific conferences and congresses in total 10 participations confirmed by programs and certificates of participation. Of which, international communications - 2, national - 8. Thesis structure. Thesis includes annotations in Romanian, Russian and English, list of abbreviations, introduction, 4 chapters with general conclusions, practical recommendations. The paper is followed by the list of bibliographical references with 222 sources and the author's CV. The introduction part of the paper reflects the topicality and scientific-practical importance of the problem addressed in the thesis, the aim, objectives, scientific novelty, theoretical importance and applied value of the research, approval of the results of the study.