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Clinical use of N-acetyl cysteine during liver transplantation: Implications of oxidative stress and inflammation as therapeutic targets.
Ntamo, Y, Ziqubu, K, Chellan, N, Nkambule, BB, Nyambuya, TM, Mazibuko-Mbeje, SE, Gabuza, KB, Orlando, P, Tiano, L, Dludla, PV
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2022;:112638
Abstract
Currently, liver transplantation is considered as the definitive treatment option for individuals with complete liver failure. However, the detrimental effects of oxidative stress and inflammation remain the predominant feature that drives hepatic ischemia-reperfusion injury during liver transplantation. As such, therapeutic drugs that hinder oxidative stress and attenuate inflammation, have become ideal targets to curb liver injuries during transplantation. The current review analyses available clinical evidence on the importance of using N-acetyl cysteine (NAC) during liver transplantation. Thus, prominent online search engines such as PubMed and Google Scholar were accessed to retrieve literature from randomized clinical trials reporting on the use of NAC during liver transplantation. Overwhelming evidence suggests that established therapeutic properties of NAC, through enhancing endogenous antioxidants like glutathione to block oxidative stress and attenuate inflammation, remain essential to improve liver function in patients undergoing liver transportation. However, to the contrary, some clinical studies did not show any beneficial effects in patients receiving NAC during liver transplantation. Thus, such controversies, in addition to discussing the implications of oxidative stress and inflammation in relation to hepatic ischemia-reperfusion injury remain the major subject of the current review.
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The role of the gut microbiome in graft fibrosis after pediatric liver transplantation.
Qin, T, Fu, J, Verkade, HJ
Human genetics. 2021;(5):709-724
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Abstract
Liver transplantation (LT) is a life-saving option for children with end-stage liver disease. However, about 50% of patients develop graft fibrosis in 1 year after LT, with normal liver function. Graft fibrosis may progress to cirrhosis, resulting in graft dysfunction and ultimately the need for re-transplantation. Previous studies have identified various risk factors for the post-LT fibrogenesis, however, to date, neither of the factors seems to fully explain the cause of graft fibrosis. Recently, evidence has accumulated on the important role of the gut microbiome in outcomes after solid organ transplantation. As an altered microbiome is present in pediatric patients with end-stage liver diseases, we hypothesize that the persisting alterations in microbial composition or function contribute to the development of graft fibrosis, for example by bacteria translocation due to increased intestinal permeability, imbalanced bile acids metabolism, and/or decreased production of short-chain fatty acids (SCFAs). Subsequently, an immune response can be activated in the graft, together with the stimulation of fibrogenesis. Here we review current knowledge about the potential mechanisms by which alterations in microbial composition or function may lead to graft fibrosis in pediatric LT and we provide prospective views on the efficacy of gut microbiome manipulation as a therapeutic target to alleviate the graft fibrosis and to improve long-term survival after LT.
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Impact of Cold Ischemia Time on the Function of Liver Grafts Preserved With Custodiol.
Rodrigues, MG, Castro, PMV, Almeida, TC, Danziere, FR, Sergi Filho, FA, Zeballos Sempertegui, BE, Branez, JR, Mota, LT, Perosa de Miranda, M, Gomes Dos Santos, R, et al
Transplantation proceedings. 2021;(2):661-664
Abstract
OBJECTIVE This study aimed to evaluate how cold ischemia time (CIT) interferes with liver graft function in the first 7 days after surgery for Custodiol (HTK) preserved organs. METHODS This retrospective observational study analyzed the medical records of 38 transplantation patients at Hospital Leforte Liberdade, São Paulo, in 2018. The study population was divided into 2 groups (group A, CIT < 8 hours; group B, CIT > 8 hours). Postoperative parameters-such as international normalized ratio, total bilirubin, aspartate aminotransferase/alanine aminotransferase, alkaline phosphatase, gamma glutamyl transferase (GGT), lactate dehydrogenase, lactate, creatinine, red blood cell transfusion, need for hemodialysis, use of vasoactive drugs, endotracheal intubation time, length of stay in the intensive care unit (ICU), and length of hospital stay-were compared. RESULTS Group A (CIT < 8 hours) presented less need for red blood cell transfusions (odds ratio 0.29; confidence interval 0.06-0.98; P = .04), had a shorter hospital stay (P = .024), and had lower levels of total bilirubin (P = .05) and GGT (P = .05) in the first 7 postoperative days. The other variables showed no statistically significant difference. CONCLUSION In livers preserved with Custodiol, CIT > 8 hours generated higher levels of total bilirubin and GGT in the postoperative period, in addition to higher hospital costs; greater need for red blood cell transfusions; and longer hospitalization, including longer stays in the ICU.
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Serum Selenium Status as a Diagnostic Marker for the Prognosis of Liver Transplantation.
Gül-Klein, S, Haxhiraj, D, Seelig, J, Kästner, A, Hackler, J, Sun, Q, Heller, RA, Lachmann, N, Pratschke, J, Schmelzle, M, et al
Nutrients. 2021;(2)
Abstract
The trace element selenium (Se) is taken up from the diet and is metabolized mainly by hepatocytes. Selenoprotein P (SELENOP) constitutes the liver-derived Se transporter. Biosynthesis of extracellular glutathione peroxidase (GPx3) in kidney depends on SELENOP-mediated Se supply. We hypothesized that peri-operative Se status may serve as a useful prognostic marker for the outcome in patients undergoing liver transplantation due to hepatocellular carcinoma. Serum samples from liver cancer patients were routinely collected before and after transplantation. Concentrations of serum SELENOP and total Se as well as GPx3 activity were determined by standardized tests and related to survival, etiology of cirrhosis/carcinoma, preoperative neutrophiles, lymphocytes, thyrotropin (TSH) and Child-Pugh and Model for End-Stage Liver Disease (MELD) scores. A total of 221 serum samples from 79 transplanted patients were available for analysis. The Se and SELENOP concentrations were on average below the reference ranges of healthy subjects. Patients with ethanol toxicity-dependent etiology showed particularly low SELENOP and Se concentrations and GPx3 activity. Longitudinal analysis indicated declining Se concentrations in non-survivors. We conclude that severe liver disease necessitating organ replacement is characterized by a pronounced Se deficit before, during and after transplantation. A recovering Se status after surgery is associated with positive prognosis, and an adjuvant Se supplementation may, thus, support convalescence.
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Domino transplantation for pediatric liver recipients: Obstacles, challenges, and successes.
Raghu, VK, Carr-Boyd, PD, Squires, JE, Vockley, J, Goldaracena, N, Mazariegos, GV
Pediatric transplantation. 2021;(8):e14114
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Abstract
BACKGROUND Domino liver transplantation aims to address the need to increase the liver donor supply. In a domino liver transplant, the domino recipient receives the explanted liver from the recipient of a traditional liver transplant. The domino donor typically requires liver transplant to correct a metabolic disorder; the explanted liver thus has a single gene defect but otherwise normal structure and function. METHODS In this review, we detail the history of domino liver transplantation, appropriate domino donor indications, the technical advances to the surgical approach, current outcomes, and future opportunities. RESULTS Development of de novo disease in the domino recipient has relegated adult domino liver transplant to be considered a source of marginal donor livers. However, pediatric domino liver transplant has leveraged certain metabolic disorders, especially maple syrup urine disease, in which the liver enzyme deficiency can be compensated by the systemic presence of sufficient enzyme. Advances in the surgical aspects of assuring adequate length of vasculature have improved the safety of the procedure in both domino donors and recipients. CONCLUSIONS Pediatric domino liver transplant utilizing domino donors with specific metabolic liver diseases should be considered a viable live donor option for children awaiting liver transplant.
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An observational study on the effect of hypercholesterolemia developed after living donor liver transplantation on cardiac event and graft failure.
Park, J, Lee, SH, Han, S, Oh, AR, Lee, SK, Choi, GS, Park, MS, Carriere, K, Ahn, J, Kim, GS
Scientific reports. 2021;(1):959
Abstract
This study sought to evaluate the association between newly-developed significant hypercholesterolemia within one year following living donor liver transplantation (LDLT) and long term outcomes in light of cardiovascular events and graft failure. From October 2003 to July 2017, 877 LDLT recipients were stratified according to development of significant hypercholesterolemia within one year following LDLT. The primary outcome was occurrence of a major adverse cardiac event (MACE), defined as a composite of cardiac death, myocardial infarction, and coronary revascularization after LDLT. The incidence of graft failure, defined as all-cause death or retransplantation, was also compared. A total of 113 (12.9%) recipients developed significant hypercholesterolemia within one year. The differences in incidences of cardiac related events and graft related events began emerging significantly higher in the hypercholesterolemia group after 24 months and 60 months since the LDLT, respectively. After adjustment using the inverse probability of weighting, the hazard ratio (HR) for MACE was 2.77 (95% confidence interval (CI) 1.16-6.61; p = 0.02), while that for graft failure was 3.76 (95% CI 1.97-7.17, p < 0.001). A significant hypercholesterolemia after LDLT may be associated with cardiac and graft-related outcome; therefore, a further study and close monitoring of cholesterol level after LDLT is needed.
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Cardiac evaluation of the kidney or liver transplant candidate.
Levy, PE, Khan, SS, VanWagner, LB
Current opinion in organ transplantation. 2021;(1):77-84
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Abstract
PURPOSE OF REVIEW As the field of transplant has advanced, cardiac events have become the leading cause of morbidity and mortality after liver and kidney transplantation ahead of graft failure and infection. This trend has been bolstered by the transplantation of older and sicker patients who have a higher burden of cardiovascular risk factors, accentuating the need to determine which patients should undergo more extensive cardiac evaluation prior to transplantation. RECENT FINDINGS Computed tomography coronary angiography with or without coronary artery calcium scoring is now preferred over stress imaging in most transplant candidates for assessment of coronary artery disease. Assessment of cardiac structure and function using transthoracic echocardiography with tissue doppler imaging and strain imaging is recommended, particularly in liver transplant candidates who are at high risk of cirrhotic cardiomyopathy, for which new diagnostic criteria were recently published in 2019. SUMMARY Cardiac evaluation of liver and kidney transplant candidates requires a global assessment for both short and long-term risk for cardiac events. Imaging of cardiac structure and function using transthoracic echocardiography with tissue doppler imaging and strain imaging is recommended. Risk stratification should consider both the anatomic and functional consequences of coronary artery disease in transplant candidates. VIDEO ABSTRACT http://links.lww.com/MOT/A27.
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Effects of both Pro- and Synbiotics in Liver Surgery and Transplantation with Special Focus on the Gut-Liver Axis-A Systematic Review and Meta-Analysis.
Kahn, J, Pregartner, G, Schemmer, P
Nutrients. 2020;(8)
Abstract
The gut-liver axis is of upmost importance for the development of infections after surgery. Further bacterial translocation due to surgery-related dysbiosis is associated with limited detoxification function of the liver compromising outcome of surgical therapy. After liver surgery, about 30% of patients develop a bacterial infection, with the risk of bacteremia or even sepsis-associated liver failure and mortality in >40%. The potential benefit of pro-/synbiotics given before surgery is still under debate. Thus, a systematic literature search on trials comparing patients with or without supplementation and outcome after liver resection or transplantation was performed. Our search strategy revealed 12 relevant studies on perioperative administration of pro-/synbiotics in liver surgery. The pro-/synbiotic combinations and concentrations as well as administration timeframes differed between studies. Five studies were performed in liver transplantation and 7 in liver resection. All studies but one reported lower infection rates (pooled RR: 0.46, 95% CI: 0.31-0.67) with pro-/synbiotics. Liver function was assessed after LT/LR in 3 and 5 studies, respectively. Pro-/synbiotics improved function in 1/3 and 2/5 studies, respectively. Concluding, perioperative pro-/synbiotics clearly reduce infection after liver surgery. However, standard protocols with both well-defined probiotic strain preparations and administration timeframes are pending.
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Post-transplant diabetes mellitus and preexisting liver disease - a bidirectional relationship affecting treatment and management.
Cigrovski Berkovic, M, Virovic-Jukic, L, Bilic-Curcic, I, Mrzljak, A
World journal of gastroenterology. 2020;(21):2740-2757
Abstract
Liver cirrhosis and diabetes mellitus (DM) are both common conditions with significant socioeconomic burden and impact on morbidity and mortality. A bidirectional relationship exists between DM and liver cirrhosis regarding both etiology and disease-related complications. Type 2 DM (T2DM) is a well-recognized risk factor for chronic liver disease and vice-versa, DM may develop as a complication of cirrhosis, irrespective of its etiology. Liver transplantation (LT) represents an important treatment option for patients with end-stage liver disease due to non-alcoholic fatty liver disease (NAFLD), which represents a hepatic manifestation of metabolic syndrome and a common complication of T2DM. The metabolic risk factors including immunosuppressive drugs, can contribute to persistent or de novo development of DM and NAFLD after LT. T2DM, obesity, cardiovascular morbidities and renal impairment, frequently associated with metabolic syndrome and NAFLD, may have negative impact on short and long-term outcomes following LT. The treatment of DM in the context of chronic liver disease and post-transplant is challenging, but new emerging therapies such as glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) targeting multiple mechanisms in the shared pathophysiology of disorders such as oxidative stress and chronic inflammation are a promising tool in future patient management.
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Portal flow modulation in living donor liver transplantation: review with a focus on splenectomy.
Yoshizumi, T, Mori, M
Surgery today. 2020;(1):21-29
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Abstract
Small-for-size graft (SFSG) syndrome after living donor liver transplantation (LDLT) is the dysfunction of a small graft, characterized by coagulopathy, cholestasis, ascites, and encephalopathy. It is a serious complication of LDLT and usually triggered by excessive portal flow transmitted to the allograft in the postperfusion setting, resulting in sinusoidal congestion and hemorrhage. Portal overflow injures the liver directly through nutrient excess, endothelial activation, and sinusoidal shear stress, and indirectly through arterial vasoconstriction. These conditions may be attenuated with portal flow modulation. Attempts have been made to control excessive portal flow to the SFSG, including simultaneous splenectomy, splenic artery ligation, hemi-portocaval shunt, and pharmacological manipulation, with positive outcomes. Currently, a donor liver is considered a SFSG when the graft-to-recipient weight ratio is less than 0.8 or the ratio of the graft volume to the standard liver volume is less than 40%. A strategy for transplanting SFSG safely into recipients and avoiding extensive surgery in the living donor could effectively address the donor shortage. We review the literature and assess our current knowledge of and strategies for portal flow modulation in LDLT.