the history of liver transplantation at the university of colorado

Zimmerman MA, Zimmerman MA, Wachs Wachs M, M, Bak Bak T, T, Kam Kam IIDivision of Transplant SurgeryDivision of Transplant Surgery

The History of Liver Transplantation at the The History of Liver Transplantation at the University of Colorado: Early Days toUniversity of Colorado: Early Days to

Live DonationLive Donation

Liver Transplantation: University of ColoradoLiver Transplantation: University of Colorado

•• New Chairman from ChicagoNew Chairman from Chicago

•• The Kidney TrialsThe Kidney Trials

•• Failed Attempts at Liver Failed Attempts at Liver Replacement Replacement

•• LongLong--term Survivalterm Survival

•• A New BeginningA New Beginning

•• Live Donor Liver TransplantLive Donor Liver Transplant

•• Arrived in Denver from Arrived in Denver from Northwestern, 1961.Northwestern, 1961.

•• Chief of Surgery, Denver VAMC.Chief of Surgery, Denver VAMC.

•• Performed the first KidneyPerformed the first KidneyTransplant in Colorado, March 27Transplant in Colorado, March 27thth, ,

1962.1962.

•• Performed first liver transplant in Performed first liver transplant in humans, March 1humans, March 1stst, 1963., 1963.

•• 19 years on faculty, last 8 years as 19 years on faculty, last 8 years as chairman.chairman.

New Chairman From ChicagoNew Chairman From Chicago

Dr. Thomas E. Dr. Thomas E. StarzlStarzl

Dr. Ben Dr. Ben EisemanEiseman•• Chief of Surgery, Denver VAMCChief of Surgery, Denver VAMC

•• Founding Chair of Dept Surgery,Founding Chair of Dept Surgery,University of KentuckyUniversity of Kentucky

•• ““Talent ScoutTalent Scout””

•• Dr. William R. Waddell Dr. William R. Waddell –– MGH to MGH to Colorado, 1961Colorado, 1961

•• EisemanEiseman returns in 1966.returns in 1966.


““Local critics of the University were fond of sayingLocal critics of the University were fond of sayingthat the Department of Surgery had a hidden that the Department of Surgery had a hidden

selfself--destruct button which activated every 10 yearsdestruct button which activated every 10 yearsor so, forcing a new start to be made, or allowingor so, forcing a new start to be made, or allowing

one, depending on the point of view.one, depending on the point of view.””


The Kidney TrialsThe Kidney Trials

1/24/19597/23/19671/2/19688/24/196811/14/19686/3/1969

BostonDenverCape TownMinneapolisGhentMinneapolis

KidneyLiverHeartBone MarrowLungPancreas

Historical firsts: Prolonged patients and allograft survival


246312181218

18017

Frat twinFrat twinUnrelatedMotherUnrelatedCousinUnrelated

1/24/19596/29/19596/22/19596/22/6012/3/19612/12/19624/5/1962

BostonParisParisParisParisParisBoston

1234567

Survival (months)

DonorDateCityNo.

Kidney transplantation: 1-year survival as of April 1963


•• Denver VAMC: Kidney transplant between identical twins.Denver VAMC: Kidney transplant between identical twins.

•• Rebuilding the laboratoryRebuilding the laboratory

•• End of 1962: Survival for one hundred days after kidneyEnd of 1962: Survival for one hundred days after kidneyTransplant could be achieved in no more than one of four Transplant could be achieved in no more than one of four

Mongrel dogs.Mongrel dogs.

•• November 24, 1962: Living related transplant, irradiation, November 24, 1962: Living related transplant, irradiation, ImuranImuran, and prednisone. , and prednisone.

•• September 1963: 30 patients had undergone kidney September 1963: 30 patients had undergone kidney txtx..


•• Kidney transplant as an illusion.Kidney transplant as an illusion.

•• 19701970’’s: Thousands of s: Thousands of cadavericcadaveric kidneys, kidneys, 1 year graft survival 1 year graft survival ≤≤ 50%.50%.

•• 6 patients given baboon kidneys, 6 patients given baboon kidneys, 100%100% rate rate of rejection.of rejection.


Starzl TE, Hepatology, 1982

Ineffective, dangerous

20-30 days pretx

Suboptimal

No Advantage

Suboptimal

Under Evaluation

Denver, Boston, Richmond

Stockholm

Denver

Denver

Cambridge

Denver

1962-3

1963

1966

1970

1978

1980

Azathioprine

Thoracic duct drain

ALG

Cyclophosphamide

Cyclosporin A

CSA + steroids

DeficienciesCityYearAgentsClinical Immunosuppressive Drug Regimens: Kidney transplant


• Fungal Extract: Trichoderman polysporum

• Biochemically characterized by Sandoz Corp., Switzerland

• Borel et al: Cyclosporin A immunosuppressive:mice, rats, guinea pigs (1977)


Starzl TE, Klintmalm GBG, Weil R, et al. Cyclosporin A and steroid therapyIn 66 cadaver kidney transplant recipients. Surg Gynecol Obstet. 1981; 153:486

80% 180% 1--yearyearsurvival following survival following cadavericcadaveric kidney kidney transplant transplant with with CyclosporinCyclosporin AAplus plus SteroidsSteroids

LONGEST SURVIVOR OF KIDNEY TRANSPLANT RECIPIENT Colorado Identical Twin transplant in 1962

Both donor and recipient are healthy in 2005

LONGEST SURVIVOR OF KIDNEY TRANSPLANT RECIPIENT Colorado Identical Twin transplant in 1962

Both donor and recipient are healthy in 2005

JW March 27, 1962 Male, age 27 (#1) Primary renal disease:

GN No prior dialysis Bilateral nephrectomy No immunosuppressant

JW March 27, 1962 Male, age 27 (#1) Primary renal disease:

GN No prior dialysis Bilateral nephrectomy No immunosuppressant


Failed Attempts at Liver Replacement

Cannon JA. Transplantation Bull, 1956; 3:7.

Starzl, Surg Gynecol Obstet, 1963

• First known efforts at experimental orthotopictransplantation of the liver

• “This report was so brief that it lacked a title, description of methods, and notation of the animal species.”


March 1, 1963March 1, 1963: First effort to replace the human liver,First effort to replace the human liver,University of ColoradoUniversity of Colorado

3 year old child: 3 year old child: ExtrahepaticExtrahepatic BiliaryBiliary AtresiaAtresia

Survival (days): 0

Main cause of death: Hemorrhage

Starzl, Surg Gynecol Obstet, 1963


Starzl, Hepatology, 1982

HemorrhagePESepsisPEHepatic failureSepsisHemorrhage

0227.56.511230

Extrahepatic BAHCCDuct cell CAHCCMetastatic Colon CAHCCMetastatic Colon CA

348685258294

DenverDenverDenverDenverBostonDenverParis

1234567

Cause of DeathSurvival(days)

DiseaseAge(yrs)

CityNo.First trials of orthotopic liver transplantation


July 23, 1967: July 23, 1967:

First extended First extended survival of a survival of a

human human recipientrecipient

OLT for HCCOLT for HCC

Survival: 13 Survival: 13 monthsmonths


May 1982: 237 patients transplanted

University of Colorado: 170

University of Pittsburgh: 67

Starzl, Hepatology, 1982

LongLong--term Survivalterm Survival

Starzl, N Engl J Med, 1981

Cyclosporin Cyclosporin AA and steroids: 1and steroids: 1--year year survival doubled to nearly survival doubled to nearly 70%70%


3 Eras of3 Eras of orthotopic orthotopic liver transplantation at theliver transplantation at theUniversities of Universities of ColoradoColorado and and PittsburghPittsburgh

Patient SurvivalPatient Survival: 1963: 1963--19931993

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are needed to see this picture.


3 Eras of3 Eras of orthotopic orthotopic liver transplantation at theliver transplantation at theUniversities of Universities of ColoradoColorado and and PittsburghPittsburgh

Graft Survival: Graft Survival: 19631963--19931993

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Abbasoglu, Transplantation, 1997

Baylor UniversityBaylor University Medical Center,Medical Center,Dallas, TexasDallas, Texas

N = 1,174N = 1,174

5yrs 5yrs 10yrs10yrsPatient 87% 71% Patient 87% 71%


Jain, Ann Surg, 2000

Figure 2.

Thomas E. Thomas E. StarzlStarzl Transplantation InstituteTransplantation InstituteUniversity of PittsburghUniversity of Pittsburgh

Pittsburgh, Pennsylvania:Pittsburgh, Pennsylvania:4,000 Consecutive Patients4,000 Consecutive Patients


Salizzoni, Transpl Int, 2005

Liver Transplantation CenterLiver Transplantation CenterSan Giovanni Battista HospitalSan Giovanni Battista Hospital

Turin, ItalyTurin, Italy

OverallOverall 1010--year Survival: 72%year Survival: 72%


Busuttil, Ann Surg, 2005

Patient 81 Patient 81 72 72 68 68 6464

Graft Graft 73 73 64 64 59 59 5555

1 yr 5yrs 10yrs 15yrs1 yr 5yrs 10yrs 15yrs

3,200 Liver Transplantations3,200 Liver Transplantations Over Two Decades:Over Two Decades:A SingleA Single--Center ExperienceCenter Experience

A New BeginningA New Beginning

“I July 1988, the colorado liver program was reborn when Alden Harken….decided to resume these efforts. We sent him Igal Kam,a talented Isreali surgeon who trained withus in Pittsburgh….A new pearl would grow from this perfect nidus. With it, my commitment to my university haven for nineteen years was fulfilled. A liver transplantprogram belonged at the University of Colorado of all places in the world.”

1,102

1,032

981 (89.0)9 (0.8)

112 (10.2)

70628

13

Total number of transplants

Number of recipients

Graft typeWhole CADSplit CADLDLT

Retransplantation - Overall2nd OLT3rd OLT

Retransplantation - LDLT2nd OLT

Number (%)Cumulative Experience to 2006Cumulative Experience to 2006


A New BeginningA New BeginningTable 1. Evolution of Liver Transplant at the University of Colorado: 1988-2006

Modification

Year

Reference (#)

Immunosuppression 1. CSA + AZA + Prednisone 2. CSA/tacrolimus + MMF + Prednisone (14 day taper) 3. CSA/tacrolimus +Prednisone (14 day taper) 4. CSA/tacrolimus +/- Prednisone 5. Sirolimus-based therapy Operative technique 1. Veno-venous bypass abandoned 2. T-tube abandoned 3. Universal extubation 4. Piggy-back technique where feasible 5. Living donor liver transplantation Antiviral therapy 1. Low accelerating dose regimen (hepatitis C)

1988 - 1995 1995 - 1997 1997 - 1999 1999 - 2000 2000 - present

1993 1994 1995 1996 1996 2005

CSA = cyclosporine; MMF = mycophenolate mofetil.

Overall Patient Survival

1yr 5yrs 10yrs91% 80% 70%


1 year: 91%1 year: 91%10 years: 70%10 years: 70%

Overall Graft Survival

1yr 5yrs 10yrs85% 74% 63%


1 year: 90%1 year: 90%10 years: 65%10 years: 65%

Overall Survival by Graft TypeOverall Survival by Graft Type


Live Donor Liver Transplant1988 Raja S, Nery JR, Mies S. Liver transplantation from liver donors. Lancet

1989;2:10421st attempt Adult to Pediatric (Lt. Lat. Seg)

1989 Strong RW, Lynch SV, Ong TH, et al. Successful liver transplantation from a living donor to her son. N Engl J Med. 1990 May 24;322(21):15051st successful Adult to Pediatric (Lt. Lat. Seg)

1994 Hashikura Y, Makuuchi M, Kawasaki S, et al. Successful living-related partial liver transplantation to an adult patient. Lancet 1994 May 14;343(8907):1233. 1st Adult Live Liver Donor Transplant (ALDLT)

1994 Yamaoka Y, Washida M, Honda K, Tanaka K, et al. Liver transplantation using a right lobe graft from a living related donor. Transplantation. 1994 (Apr 15;57(7):1127. 1st right lobe (ALDLT)

1997 Lo CM, Fan ST, Liu CL, Wei WI, et al. Adult-to-adult living donor liver transplantation using extended right lobe grafts. Ann Surg. 1997 Sep:226(3):261.

1997 Wachs M, Bak T, Karrer F, Everson G, et al. Adult living donor liver transplantation using a right hepatic lobe. Transplantation. 1998:10(66):1313. 1st right lobe in the Western Hemisphere

1998 Accumulative ExperienceMarcos, Miller, Broelsch, and others

19881988 Raja S, Raja S, Nery Nery JR, JR, Mies Mies S. Liver transplantation from liver donors. Lancet S. Liver transplantation from liver donors. Lancet 1989;2:10421989;2:104211stst attempt Adult to Pediatric (Lt. Lat. attempt Adult to Pediatric (Lt. Lat. SegSeg))

19891989 Strong RW, Lynch SV, Strong RW, Lynch SV, Ong Ong TH, et al. Successful liver transplantation from a TH, et al. Successful liver transplantation from a living donor to her son. N living donor to her son. N Engl Engl J Med. 1990 May 24;322(21):1505J Med. 1990 May 24;322(21):150511stst successful Adult to Pediatric (Lt. Lat. successful Adult to Pediatric (Lt. Lat. SegSeg))

19941994 Hashikura Hashikura Y, Y, Makuuchi Makuuchi M, Kawasaki S, et al. Successful livingM, Kawasaki S, et al. Successful living--related related partial liver transplantation to an adult patient. Lancet 1994 partial liver transplantation to an adult patient. Lancet 1994 May May 14;343(8907):1233. 14;343(8907):1233. 11stst Adult Live Liver Donor Transplant (ALDLT)Adult Live Liver Donor Transplant (ALDLT)

19941994 Yamaoka Y, Yamaoka Y, Washida Washida M, Honda K, Tanaka K, et al. Liver transplantation M, Honda K, Tanaka K, et al. Liver transplantation using a right lobe graft from a living related donor. Transplanusing a right lobe graft from a living related donor. Transplantation. 1994 tation. 1994 (Apr 15;57(7):1127. (Apr 15;57(7):1127. 11stst right lobe (ALDLT)right lobe (ALDLT)

1997 1997 Lo CM, Fan ST, Liu CL, Wei WI, et al. AdultLo CM, Fan ST, Liu CL, Wei WI, et al. Adult--toto--adult living donor liver adult living donor liver transplantation using extended right lobe grafts. Ann transplantation using extended right lobe grafts. Ann SurgSurg. 1997 . 1997 Sep:226(3):261. Sep:226(3):261.

19971997 Wachs M, Bak T, Karrer F, Everson G, et al. Adult living donor lWachs M, Bak T, Karrer F, Everson G, et al. Adult living donor liver iver transplantation using a right hepatic lobe. Transplantation. transplantation using a right hepatic lobe. Transplantation. 1998:10(66):1313. 1998:10(66):1313. 11stst right lobe in the Western Hemisphereright lobe in the Western Hemisphere

19981998 Accumulative ExperienceAccumulative ExperienceMarcos, Miller, Broelsch, and othersMarcos, Miller, Broelsch, and others

Live Donor Liver Transplant

Recipient Surgery

Hepatico- Jejunostomy


0

100

200

300

400

500

600

89 90 92 94 96 98 2000 2001 2002 2003 2004

yr

0

100

200

300

400

500

600

89 90 92 94 96 98 2000 2001 2002 2003 2004

yr

U.S. LDLT volumeU.S. LDLT volume

X


Country Estimated number LDLT

US 2889

Europe 1709

Asia 1508

Brazil 132

Total 6238

LDLT World ActivityLDLT World ActivityLDLT World Activity


0102030405060708090

100

95 97 99 2001 2003 2005

LDLTOLT-AdultOLT-Pediatric

0102030405060708090

100

95 97 99 2001 2003 2005

LDLTOLT-AdultOLT-Pediatric

CU LDLT ExperienceCU LDLT Experience


0%5%

10%15%20%25%30%35%

1998 1999 2000 2001 2002 2003 2004 2005

yr

USCU

0%5%

10%15%20%25%30%35%

1998 1999 2000 2001 2002 2003 2004 2005

yr

USCU

U.S. LDLT volumeU.S. LDLT volumeU.S. LDLT volume


Deaths “definitely” to donor hepatectomy = 11

Death rate = 11/6238 = 0.18 %

Deaths “definitely or possibly” to donor hepatectomy = 13

Death rate = 13/6238 = 0.21 %

Donor DeathDonor DeathDonor Death

Outcomes of 385 Adult-to-AdultLiving Donor Liver Transplant Recipients:

A Report from the A2ALL Consortium

Outcomes of 385 AdultOutcomes of 385 Adult--toto--AdultAdultLiving Donor Liver Transplant Recipients: Living Donor Liver Transplant Recipients:

A Report from the A2ALL ConsortiumA Report from the A2ALL Consortium

K. Olthoff, R. Merion, R. Ghobrial, M. Abecassis, J. Fair, R. FiK. Olthoff, R. Merion, R. Ghobrial, M. Abecassis, J. Fair, R. Fisher, C. Freise, I. Kam,sher, C. Freise, I. Kam,T. Pruett, J. Everhart, T. HulbertT. Pruett, J. Everhart, T. Hulbert--Shearon, B. Gillespie, and J. EmondShearon, B. Gillespie, and J. Emond

Presented at ASA April 2005 by K. Olthoff for A2ALLPresented at ASA April 2005 by K. Olthoff for A2ALLAnn Surgery 2005Ann Surgery 2005

Live Donor Liver TransplantLive Donor Liver Transplant


Robert Fisher, MDRobert Fisher, MDRichmond, VARichmond, VAVirginia CommonwealthVirginia CommonwealthCarl Berg, MDCarl Berg, MDCharlottesville, VACharlottesville, VAUniversity of VirginiaUniversity of VirginiaAbraham Shaked, MDAbraham Shaked, MDPhiladelphia, PAPhiladelphia, PAUniversity of PennsylvaniaUniversity of PennsylvaniaJeff Fair, MDJeff Fair, MDChapel Hill, NCChapel Hill, NCUniversity of North CarolinaUniversity of North CarolinaRobert Merion, MDRobert Merion, MDAnn Arbor, MIAnn Arbor, MIUniversity of Michigan*University of Michigan*James Trotter, MDJames Trotter, MDDenver, CODenver, COUniversity of ColoradoUniversity of ColoradoChris Freise, MDChris Freise, MDSan Francisco, CASan Francisco, CAUniversity of CaliforniaUniversity of California

R. Mark Ghobrial, MDR. Mark Ghobrial, MDLos Angeles, CALos Angeles, CAUniversity of CaliforniaUniversity of California

James Everhart, MDJames Everhart, MDBethesda, MDBethesda, MDNIH/NIDDKNIH/NIDDK

M Abecassis, MDM Abecassis, MDChicago, ILChicago, ILNorthwestern UniversityNorthwestern University

Jean Emond, MDJean Emond, MDNew York, NYNew York, NYColumbia UniversityColumbia UniversityPrincipal InvestigatorPrincipal InvestigatorLocationLocationCenterCenter

A2ALL ParticipantsA2ALL ParticipantsA2ALL Participants


Graft survival improved with higher case numbers– Significantly decreased risk after 20

cases Biliary complications decreased with

higher case numbers– Bile leaks decreased significantly after

20 cases Cold ischemia time decreased

steadily with higher case numbers

Graft survival improved with higher case numbers– Significantly decreased risk after 20

cases Biliary complications decreased with

higher case numbers– Bile leaks decreased significantly after

20 cases Cold ischemia time decreased

steadily with higher case numbers

The Learning CurveThe Learning CurveThe Learning Curve

University of Colorado Health Sciences CenterUniversity of Colorado Health Sciences Center

the history of liver transplantation at the university of colorado

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