Liver Transplantation at SLEH/BCM John A. Goss, MD Professor of Surgery Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas

History of Transplantation 1902 1983 1963 1936 1954 2002 1998 1994 1989 First attempt at kidney transplant First attempt at kidney transplant with human kidney First pediatric living donor liver transplant Cyclosporine FDA approved First liver transplant First successful kidney transplant First US adult living donor liver transplant Tacrolimus FDA approved MELD implemented

Initial Kidney Transplant Attempts: Year Location Surgeon Procedure 1902 Lyon Alex Carrel Dog kidney tx into dog neck Vienna Emerich Ulmann Dog kidney tx into goat 1906 Mathieu Jaboulay Pig kidney tx into antecubital fossa 1909 Berlin Ernest Unger Monkey kidney tx into thigh 1936 Kherson Yu Voronoy First kidney tx using cadaveric human donor 1954 Boston Joseph Murray First successful kidney tx 1956 First tx using immunosuppression

First Successful Kidney Transplant

Experimental Liver Transplantation text

Initial Liver Transplant Attempts: 1963-1964 No. Location Age Disease Survival Death 1 Denver 3 BA 0 days hemorrhage 2 48 HCC 22 days sepsis, PE 68 7 days 4 52 6 days liver failure 5 Boston 58 mets. 11 days sepsis 6 29 23 days 7 Paris 75

Initial Liver Transplant Attempts:

First Liver Transplant March 1, 1963: First attempted human liver transplant July 23, 1967: First successful human liver transplant

Post-Moratorium Successes anti-lymphocyte globulin (ALG) & the “triple cocktail” improved organ preservation definition of “brain death” text Starzl TE. J Am Coll Surg 2002; 195:587.

1968 Ad Hoc Committee of Harvard Medical School Published Criteria for Brain Death 1968 Uniform Anatomical Gift Act 1978 Uniform Brain Death Act 1983 NIH Consensus Development Conference: “…Liver Transplantation is a therapeutic modality for end stage liver disease that deserves broader application.” 1984 National Organ Transplant Act: Sale of organs prohibited Development of UNOS

Indications for Liver Transplant Life-threatening and progressive irreversible liver disease Fulminant hepatic failure Hepatopulmonary or hepatorenal syndrome Worsening synthetic function Ascites resistant to medical therapy Hepatic encephalopathy Variceal hemorrhage Progressive malnutrition Increasing fatigue that interferes with daily activities Recurrent cholangitis Development of hepatocellular carcinoma

Etiology of Liver Disease

Indication for Liver Transplantation Evaluation Process Hepatologist Transplant Surgeon Cardiologist Nurse Coordinator Social Worker Laboratory Studies Imaging (CT or MRI) List for Transplant Absolute Contraindications Uncontrolled systemic infection Extra-hepatic malignancies Ongoing drug or alcohol use Inability to comply with post-transplant therapy Relative Contraindications Portal vein thrombosis Pulmonary hypertension Cholangiocarcinoma HIV Medical Management

Liver Waitlist

Organ Allocation 2002-present Timing of Transplant Organ Allocation 2002-present MELD (Model of End Stage Liver Disease) Originally developed to evaluate mortality in patients undergoing elective TIPS procedures Subsequently validated as predictive of survival in patients with end stage liver disease 85% of time accurately predicts individuals survival Only objective data used in calculation

MELD MELD 3 Month Mortality <10 2-8% 10-19 6-29% 20-29 50-76% 30-39 R= (0.957 x Loge(creatinine mg/dl) + 0.378 x Loge(total bilirubin mg/dl) + 1.120 x Loge(INR) + 0.643)) x 10 MELD 3 Month Mortality <10 2-8% 10-19 6-29% 20-29 50-76% 30-39 62-83% >40 100%

Liver Allocation Status IA Status IB Local MELD/PELD Regional MELD/PELD National IA/IB National MELD/PELD

Deceased Donor Technique

Recipient Technique: Liver

Recipient Technique: Liver

Immunosuppression

Improvement in Patient Survival Time After Transplantation (years)

Improvement in Allograft Survival Time After Transplantation (years)

US Survival: Adult Liver

US Survival: Pediatric Liver

Liver Transplantation - BCM initiated Recruitment in 1998 1 Hepatologist, 2 Surgeons, 1 Nurse Coordinator 1 Social Worker, 1 Financial Coordinator, HLA Blood Bank, etc. Development of Patient Care Protocols – ICU, Anesthesia, OR Nurse Obtainment of UNOS Certification 6/98

Liver Transplantation - Opened program 7/1/98 – combined with pediatric program at Texas Children’s Hospital 1st resection 7/5/98 1st liver transplant 9/2/98 9 liver transplants in 1998 - All patients survived with 14 day length of stay

Liver Transplantation- 17 Physicians - 9 Adult Hepatologists 6 Pediatric Hepatologists 2 Surgeons 14 Nurse Coordinators 5 Hepatology Nurses 5 Medical Assistants 2 Administrative Staff 3 Transplant programs

SLEH Liver Transplant Team SLEH/BCM Administration Margaret Van Bree, MHA, DrPH Paul Klotman, MD Todd Rosengart, MD Rachel Goldsmith, MPA Diesa Samp, BSN, RN, CCTC Physicians John Goss – BCM Blaine Hollinger-BCM Khozema Hussein-BCM Prasun Jalal-BCM Saira Khaderi-BCM Charles Phan-BCM Christine O’Mahony- BCM Gagan Sood, BCM Rise Stribling- BCM Norman Sussman-BCM John Vierling- BCM THI Anesthesiology C. David Collard, MD Cardiology Sayeed Feghali, MD THI Pathology/Blood Bank/ Lab Med Rhonda Shannon, MD Psychiatry Jennifer Pate, M.D. Pulmonary, Nephrology, Infectious Diseases, GI THI Nurse Coordinators Claudette Campbell, RN Jeanette Cleveland, RN Shannon Cook, RN Norma Flores, RN Felicia Franco, RN Diana Gonzalez, RN Demetrice Gray, RN Yolanda Murray, RN Wanda Samuels, RN Tamara Stephens, RN Pharmacy Raymond Yau, PharmD Social Work Ann Holder, LCSW Robin Kremer, LCSW Dietary Amy Cook, RD Financial Deidra Lester Exercise Physiologist Fabian Nursing Staff: CVOR, CV Recovery, 8CB 12 & 7 Tower

Diagnosis

Primary Payor 15% 33% 3% 48%

Transplant Totals 120 114 110 105 105 119 95 94 85 83 73 66 66 67 51 12

2010: One Thousand Liver Transplants 2010 Adult Liver Transplant Team

Patient Survival

* * * *Statistically higher than expected Graft Survival

2012 Summary Unadjusted patient and graft survival: 98% Median length of stay: 9 days Operative time: 3 hours and 20 minutes Number of blood transfusions: 1.7 units of PRBCs

Future Directions Asian Liver Center Outreach clinics Improvement in length of stay Improvement in survival Telemedicine/ECHO

Liver Transplantation – Education/Research Provide Clinical Environment for BCM 3rd Year Medical Student and BCM General Surgery Residents TSMBE and ASTS Approved Liver Transplant Fellowship AASLD Funded NP Fellowship Trained Murat Kilic, MD – Chief of Liver Transplantation Izmir, Turkey 108 Peer-reviewed publications 102 National oral presentations TSMBE/ACGME Hepatology Fellowship

Liver Transplant Division: Ongoing Research Projects Research Division Post-transplant Lymphoma Hepatocellular carcinoma Clinical Research

Status of Tissue Bank >1400 tissue samples from 146 patients Sanger Sequencing of HCC Samples 300 amplicons over 30 genes 89 HCC samples with matched non tumor tissue or blood 33 HCV, 3 EtOH, 1 BA, 49 HBV, 3 with no underlying liver disease 16 Hepatoblastoma with non tumor tissue 4 Hepatic adenoma with non tumor tissue

Ongoing Projects Epigenetics of HCC Gene expression profiling Investigating differential methylation patterns in tumor and non tumor tissue Gene expression profiling Developing cDNA libraries from mRNA Whole genome sequencing Select patients to have entire genome sequenced Testing new platforms New Next Generation sequencers to be tested on HCC samples Development of collaborative tissue exchange programs Vanderbilt, Baylor Dallas, Harvard, and Mayo Clinic participating in the early stages of the development of an HCC consortium

Future Reduce Donor/Recipient Discrepancy Donor awareness campaigns Extended criteria/ asystolic donors Split liver transplantation Living-donor liver transplantation Xenotransplantation

Future Bioartificial Liver Stem Cells

Future Tolerance

Future Personalized Immunosuppression Increase selectivity, decrease toxicity/side effects Pediatric transplantation Hepatitis C Coinfection

Future Pharmacogenetics and Pharmacogenomics

Future Primary Liver Tumors Hepatocellular carcinoma that exceeds Milan Criteria Down-staging Presence of vascular invasion Genetics Choangiocarcinoma Previously considered a contraindication to OLT Mayo Protocol: multimodality neoadjuvant therapy

Conclusion Liver transplantation has produced a positive impact on patients with advanced liver disease Spectacular improvement have occurred since the preliminary work of Dr. Starzl The advances in liver transplantation have occurred in a short 45 years and provide a base for future advances