الفهرس 
I. Introduction and Aim of the studyOnly 14 pages are availabe for public view
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Abstract
”Liver disease causes two million deaths each year, accounting for 4% of all fatalities. The primary reasons for these deaths are complications arising from cirrhosis and hepatocellular carcinoma (HCC). Globally, viral hepatitis, alcohol consumption, and non-alcoholic fatty liver disease are the leading causes of cirrhosis.
Liver transplantation (LT) has been accepted as a standard treatment providing the chance of survival for patients with acute liver failure or end- stage chronic liver diseases, and improvement in patients’ life expectancy. The practice of LT has made remarkable progress over the last decades. The most frequent complications are acute or chronic rejection, leading to acute or chronic allograft dysfunction and subsequent graft fibrosis.In Egypt, living donor liver transplant (LDLT) was first performed in Egypt in 1991.The total number of cases reached 5,500 by the end of 2022. The vast majority of indications were HCV hepatitis. Graft failure outcomes were 6.1%, 8.7% in 6 months and 12 months for LDLT respectively.Allograft fibrosis remains a common complication after LT and is defined as the excessive remodeling and accumulation of extracellular matrix (ECM) proteins (including collagen) within the transplanted liver.Liver allograft fibrosis is one of the main determinants of allograft survival and the need for re-transplantation; therefore, early recognition of fibrosis is of great clinical interest in the management of LTR. Patients with LT can have many risk factors for fibrosis recurrence after LT. Such as, consequence of HCV infection had almost universal recurrence of HCV infection with the development of cirrhosis post-LT.In addition, due to the higher incidence of metabolic syndrome (MetS) after LT, recurrence or de novo NAFLD after LT is an important cause of recurrent fibrosis after LT. Furthermore, there are other factors that may negatively influence fibrosis recurrence after LT, such as demographic factors (i.e., recipient and donor age), immunosuppressive therapy, and cytomegalovirus infection. Liver biopsy (LB) remains the most widely utilized method for diagnosis of allograft rejection following LT. Knowing the challenges related to sampling error, interpretation variability, significant costs and repeatability, the major limitation in the performance of LB is the risk of complications and generally poorly accepted by patients. The clinical feasibility and prolonged monitoring of LB in LTR have been relatively limited. However, associated risks and limitations present an opportunity for emerging noninvasive diagnostic techniques to improve upon the current standard of care and this allows the opportunity for noninvasive methods as a screening and monitoring method for subclinical changes in liver grafts after LT. Moreover, it is more suitable for continuous monitoring of graft fibrosis in the LT populations. An accelerated course of hepatic fibrosis may occur in LT patients despite normal or slightly abnormal liver blood tests, indicating an urgent need for predictive non-invasive methods (biomarkers/imaging) to detect serious graft dysfunction. ECM biomarkers, as discussed for other markers, provide a more dynamic assessment of the fibrotic response to injury or inflammation and correlate closely with the severity of liver disease by measuring both the formation and degradation of ECM protein fragments in plasma. In this regard, ECM biomarkers as a dynamic tool to assess ongoing fibrogenesis induced by graft injury or inflammation, could complement the diagnostic work-up of LTR and help to identify patients with moderate fibrosis and ongoing necro inflammatory activity sustaining fibrogenesis who could benefit from modification of immunosuppressive management. Detecting patients with early post-transplant fibrosis after LT is very important. Non-invasive tests are needed to avoid liver biopsies. Therefore, our study was aimed to assess the presence of allograft fibrosis in LTR 3- and 6 months post LT through the biochemical laboratory tests and using ECM remodeling biomarkers. Moreover, one of the aims of our study was to detect HCV recurrence in patients with LDLT who achieved sustained virological response (SVR), to detect risk factors associated with the development of HCV, as well as to detect the impact of HCV infection recurrence on both patients and graft after LT.To achieve our aims, we collected blood samples from 37 patients had LDLT who used SVR and 30 apparently healthy volunteers were chosen as control. All included patients and control group were subjected and monitored for: -1-liver enzymes (ALT, AST, Bil, ALP, and INR).2-Platelet count was determined through testing complete blood count while aspartate aminotransferase ratio index (APRI) score was calculated by using the formula, [(AST/ULN)/platelet counts (109 /L)] ×100.3-Detection of fibrotic ECM biomarkers as Co1 III, LAM and HA using ELISA.4- Detection of HCV RNA by RT PCR technique after 3 months from LDLT.The following results were obtained: -1.The main demographic characteristics of LDLT patients and healthy controls-The patient’s age ranged from 18 to 65 years while the age of control group ranged from 21 to 48 years. The mean age of the patients was 45.6± 15.3 years, most of them (26/37) were men (70.3%), while the mean age of control group was 34.3 ± 8.8 years. A significant difference was p<0.001 and p = 0.03 for age and gender of patients in comparison to control group.- ALT and AST activities were elevated for patients - 3 and 6 months post LT- than that of the control group (86.5 ± 85, 63.7 ± 49.7 vs 21.7± 3.2 U/lfor ALT and 84.5±91.5, 60.4±40.7 and 21.6±2.2 for AST) for 3 months, 6 months and control group respectively with p< 0.001. Also, Bilirubin, ALP and APRI score was higher in patients group compared to control one with p<0.001. On the same manner, APRI score was comparable in case of patient groups according to control one (1.5±1.4, 2.7±8.1 vs 0.25 ±0.10) for 3-, 6- months post LT patients and controls respectively with p< 0.001.
Similarly, liver enzyme levels for patients 3 months post LT were higher than that after 6 months (86.5 U/l vs 63.7 U/l, 84.5 U/l vs 60.4 U/l and 2.4 mg/dl vs 1.7 mg/dl in case of ALT, AST and Bilirubin respectively while there was no clearance difference in case of both INR (1.38 vs 1.32, p=0.65) and ALP (8.2 vs 8.7 U/l, p=0.6).2. Fibrosis markers of LDLT patients and healthy controls and HA were all significantly increased (P<0.001) 3- months post LT compared to that of 6 months post LT. Since the levels of 3 months post LT for COl, LAM and HA were 16.6±12.1 ng/ml, 64±16.8 ng/ml and 114.2±23.5 ng/ml compared to 5.1±3.1, 55±16.7 and 94.1±28.6 ng/ml for 6 months post LT for the three parameters respectively.- On the other hand, levels of these parameters were more elevated in patients group compared to that in control one (1.85±0.7, 31.1±11, 66.1±22.8 for COl, LAM and HA for control group respectively) (P<0.001).3.Comparison between HCV recurrence and non recurrence patients- Sever HCV recurrence was noted after 3 months post LT and showed a 32.4% (12/37) of the case had HCV recurrence. This percentage was elevated to 45.9% after 6 months.-The values of ALT, AST, Bil and INR were significantly differenced as 157.5 U/l Vs 52.4 U/l (p<0.001), 153.2 U/l vs 51.5 U/l (p<0.001), 4.7 mg/dl vs 1.1mg/dl (p<0.001) and 2.1vs 1.28 (p<0.001) for recurrence and non recurrence respectively. On the other hand (contrary), the was not variable difference between the values of ALP for the two groups (8.4 ±2.6 vs 8.1±4.3, p = 0.7) for recurrence and non recurrence respectively.-APRI score was high in case of recurrence patient compared to that of non recurrence 3 months post LT (2.7 vs 0.88 % for recurrence and non recurrence respectively, p < 0.001).4. Rejection LT for recurrence patients-Out of 12 HCV recurrence patients, four had acute cell rejection (33.3%), five (41.7%) were advanced fibrosis, 2 (16.7 %) were cirrhosis and only one case was intact liver architecture (8.3%).-Levels of COl, LAM and HA parameters in recurrence was higher than that of non recurrence, since the levels of COL, LAM and HA for recurrence group were 25.57±11.64 ng/ml, 70.76±19.8 ng/ml and 125.84±24.59 ng/ml compared to 12.31±9.82, 60.75±2.88 and 108.56±21.14 ng/ml for non recurrence for the three parameters respectively ROC Curve between control and patients -AUC was 0.903, 0.931 and 0.860 for COl, LAM and HA respectively with p< 0.001 for the parameters. On the same road positive predictive value (PPV) were 96.8, 94.6 and 92.3 for COl, LAM and HA respectively which reflect the accuracy of the diagnostic test. VI.2. Conclusion In conclusion, our study explores the potential capability of ECM biomarkers (Col, LAM and HA) as promising surrogates for non- invasively assessing the presence of relevant graft fibrosis and ongoing fibrogenesis. ECM biomarkers have been shown primarily to identify patients with early fibrotic changes 3- and 6- months post LT who could potentially benefit from targeted therapeutic interventions, particularly an increase or change in immunosuppression. ECM biomarkers, provide a more dynamic assessment of the fibrotic response to injury or inflammation, and correlate closely with the severity of liver disease by measuring the liver enzymes which reflect the function and work- up of the transplanted graft of LTR and with the calculation of APRI score avoiding the invasive LB technique. Also, this result demonstrated the negative effect of the HCV recurrence on allograft post LT which lead to graft dysfunction and hence to graft rejection.