The major portion of this proposal involves the in-depth examination of factors that affect the ability of liver tissue to regenerate after live donor hepatectomy or receipt of a partial liver allograft in a living donor liver transplant (LDLT). In animal models, the A20 gene complex has been shown to be involved in hepatic regeneration after lethal hepatectomy, and in humans, polymorphism in A20 have been identified as susceptibility loci for several inflammatory and autoimmune diseases. These studies will determine if A20 polymorphism and level of expression in donor liver may serve as reliable prognostic markers for successful LDLT. The following studies will be performed: 1) A20 polymorphisms in LDLT donors will be probed for using single nucleotide polymorphisms using donor peripheral blood cells;2) Pre- and post-perfusion liver biopsies will be obtained at the time of transplant and whenever required by clinical situation. A20 mRNA will be determined by quantitative PCR, its cellular distribution will be determined by immunohistochemistry, and levels of priming cytokines and growth factors will be measured;3) Biological and molecular markers will be examined in LDLT donor and recipients on days 1, 3, 5, and 7 post-transplantation/donation and whenever readmitted to hospital;4) Data will be correlated with clinical course and hepatic regeneration as determined by MeVis reconstruction of volumetric CT examination.
The second aim will investigate the role of portal hypertension in the development of small for size syndrome after LDLT. The incidence will be determined by direct measurement of portal pressure and procedures to reduce pressures will be investigated. Outcomes including development of small for size syndrome, hepatic regeneration, and adverse outcomes including death and need for re-transplantation will be analyzed. The effect of hepatic regeneration on LDLT donors will be examined by comparing results of validated quality of life instruments with CT volumetric determinations of hepatic regeneration at 1, 2, and 5 years after donation. Finally the effect of donor and recipient socioeconomic factors on access to LDLT will be studied.

Public Health Relevance

These studies will integrate the expertise of clinicians, basic scientists, and clinical researchers and have potential to identify A20 based therapies useful for the prevention or treatment of liver graft dysfunction, identify and devise treatment strategies for portal hyperperfusion, identify effect of hepatic regeneration on donor quality of life, and demonstrate socioeconomic factors that enhance or impede access to LDLT.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZDK1)
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Sherker, Averell H
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Lahey Clinic
United States
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Dew, Mary Amanda; Butt, Zeeshan; Liu, Qian et al. (2018) Prevalence and Predictors of Patient-Reported Long-term Mental and Physical Health After Donation in the Adult-to-Adult Living-Donor Liver Transplantation Cohort Study. Transplantation 102:105-118
Butt, Zeeshan; DiMartini, Andrea F; Liu, Qian et al. (2018) Fatigue, Pain, and Other Physical Symptoms of Living Liver Donors in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study. Liver Transpl 24:1221-1232
Butt, Z; Dew, M A; Liu, Q et al. (2017) Psychological Outcomes of Living Liver Donors From a Multicenter Prospective Study: Results From the Adult-to-Adult Living Donor Liver Transplantation Cohort Study2 (A2ALL-2). Am J Transplant 17:1267-1277
Levitsky, Josh; Goldberg, David; Smith, Abigail R et al. (2017) Acute Rejection Increases Risk of Graft Failure and Death in Recent Liver Transplant Recipients. Clin Gastroenterol Hepatol 15:584-593.e2
DiMartini, A; Dew, M A; Liu, Q et al. (2017) Social and Financial Outcomes of Living Liver Donation: A Prospective Investigation Within the Adult-to-Adult Living Donor Liver Transplantation Cohort Study 2 (A2ALL-2). Am J Transplant 17:1081-1096
Baker, Talia B; Zimmerman, Michael A; Goodrich, Nathan P et al. (2017) Biliary reconstructive techniques and associated anatomic variants in adult living donor liver transplantations: The adult-to-adult living donor liver transplantation cohort study experience. Liver Transpl 23:1519-1530
Emond, Jean C; Goodrich, Nathan P; Pomposelli, James J et al. (2017) Hepatic Hemodynamics and Portal Flow Modulation: The A2ALL Experience. Transplantation 101:2375-2384
Mandell, M Susan; Smith, Abigail R; Dew, Mary Amanda et al. (2016) Early Postoperative Pain and its Predictors in the Adult to Adult Living Donor Liver Transplantation Cohort Study. Transplantation 100:2362-2371
Dew, Mary Amanda; DiMartini, Andrea F; Ladner, Daniela P et al. (2016) Psychosocial Outcomes 3 to 10 Years After Donation in the Adult to Adult Living Donor Liver Transplantation Cohort Study. Transplantation 100:1257-69
Gordon, Fredric D; Goldberg, David S; Goodrich, Nathan P et al. (2016) Recurrent primary sclerosing cholangitis in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study: Comparison of risk factors between living and deceased donor recipients. Liver Transpl 22:1214-22

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