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Transplantation of isolated liver cells in the treatment of liver-based metabolic disease PowerPoint Presentation

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Description : This medical presentation is about transplantation of isolated liver cells in the treatment of liver-based metabolic disease. It provides information on organ transplantation, transplantation and PKU, liver transplantation and surgical risks (Risk of Graft Loss), and pediatric liver transplantation..

Tags : Extra-Hepatic Morbidity, Treatment of PKU, Phenylalanine, protein restriction, monitoring of Phe levels, PKU Diet, Consequences of Hyperphe, Maternal PKU, Cell transplantation, Invasive Therapy, Crigler-najjar syndrome, Hepatocyte transplantation, LBMD, Risk, liver irradiation, infants

Published on : Apr 21, 2021 | Views : 991 | Downloads : 1

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Slide 1-

TRANSPLANTATION OF ISOLATED LIVER CELLS IN THE TREATMENT OF LIVER-BASED METABOLIC DISEASE
Slide 2-

Transplantation and PKU Organ Transplantation Most people view transplantation as very risky, expensive, and experimental Questionable quality of life from immune suppression PKU Most definitions of "well controlled" allow Phe levels well above normal Approximately half of patients who use Kuvan (biopterin) respond Most do so only partially Typical adult dose is 10 pills/day at about $80,000 per year PEG-PAL (enzyme replacement) will require weekly injections Probable adult cost: several hundred thousand dollars/year
Slide 3-

LIVER TRANSPLANTATION Surgical Risks Risk of Graft Loss It is no longer 1984!
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Long Term Results of Liver Transplantation 1996-2007 Data from Children’s Hospital of Pittsburgh All Etiologies of Liver Disease
Slide 5-

Outcomes of >5 Year Survivors of Pediatric Liver Transplantation: SPLIT Pediatric Academic Multi-Organ Transplantation (PAMOT) Program Hospital for Sick Children, Toronto, Canada And EMMES Corporation, Rockville, MD, USA Study population (N=461 Children) 54% < 2 years old - 30% > 13 years old (13% LBMD; 11% ALF; 4% Tumor; 47% BA) 87% of patients still have first graft Infection PTLD (6%) Growth and development Height below 10% percentile - 29% Weight below 10% percentile - 18%
Slide 6-

Extra-Hepatic Morbidity at the 5-Year Anniversary % of patients cGFR < 90 HTN  BMI  choles triglyceride
Slide 7-

Treatment of PKU Phenylalanine (protein restriction) Close monitoring of Phe levels Watch for unexpected Phe sources Life long therapy
Slide 8-

PKU Diet Highly restrictive Socially and financially burdensome Time consuming to manage Medical and low protein foods are unpalatable to some Problems with adherence Diet for life!
Slide 9-

Consequences of Hyperphe When PKU is untreated: Mental retardation or loss of IQ Seizures Difficulties in executive function Psychological and behavioral issues Social difficulties Tremors Irritability Eczema Children When PKU is poorly controlled: Difficulties in executive function Psychological and behavioral issues Social difficulties Neurological complications Irritability Eczema Adults PKU Patients Not on Diet
Slide 10-

Maternal PKU Risk of fetal damage is extremely high in uncontrolled women (Phe > 20) 92% mental retardation 72% microcephaly 40% IUGR 12% congenital heart disease Risks are lower with lower Phe What is the critical threshold level?
Slide 11-

CELL TRANSPLANTATION Minimally Invasive Therapy for Life-Threatening Diseases
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CRIGLER-NAJJAR SYNDROME TYPE 1 HEPATOCYTE TRANSPLANTATION: LBMD BILIRUBIN: FELL FROM 27 TO 12 MG/DL PHOTOTx: REDUCED 30-40% B-UGT ACTIVITY: 0.4 TO 5.5% NORMAL BILE: 33% BILI GLUCURONIDES Recessively Inherited Absence of Bilirubin-UGT Unconjugated Hyperbilirubinemia Kernicterus BILIRUBIN 30 mg/dl 0 mg/dl DAYS 150 -30
Slide 13-

HEPATOCYTE TRANSPLANTATION CRIGLER-NAJJAR SYNDROME TYPE 1
Slide 14-

CRIGLER-NAJJAR SYNDROME TYPE 1 HEPATOCYTE TRANSPLANTATION HUMAN GUNN RAT LIVER-BASED METABOLIC DISEASE
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HEPATOCYTE TRANSPLANTATION Treatment of Children in LBMD Conditioning Regimen: Liver-Directed RT to Right Liver Lobe (Conditioning Similar to that Required for Bone Marrow Transplantation)
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8- 7- 6- 5- 4- 3- 2- 1- 0- 0 4 8 12 16 Serum Bilirubin Levels (mg/dl) Time after Hepatocyte Transplantation (Weeks) 20 24 28 Regional RT Followed by Hepatocyte Transplantation Correction of Bilirubin levels in Gunn Rat model of CN-1 − HIR (ML) + Ad-HGF + HT (n=6) - RT to ML + LL (~60% of liver; n-8) - no RT (n = 4) - RT to ML (~35% of liver; n = 6)
Slide 17-

RISK OF LIVER IRRADIATION IN INFANTS RT for Liver Hemangiomas - 1950s to 1980s 1/3 liver can tolerate up to 10,000 Rads 20 Liver Cancer Rare After Liver-Directed RT National Wilm’s Tumor Study - 2438 patients Minimal Cancer Risk Associated with High Dose RT and Chemotherapy
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PKU AND TRANSPLANTATION Liver Cell Transplantation Providing a small percentage (5-10%) of normally functioning liver cells should provide normal PKU control with a normal diet Sarkissian CN, et al Molec Genet and Metab 69; 188, 2000 Hamman K et al Molec Ther 12; 337, 2005 If immune suppression becomes an issue, it can be stopped and the native liver still functions perfectly aside from the PAH defect
Slide 19-

The Jury Is Out