In July 1988, the liver and pancreas of a cadaveric donor were transplanted separately into a man with type 1 diabetes with end-stage chronic hepatitis B virus. Two features of the operation may help explain the patient's current status as the longest-lived liver-pancreas recipient. One was enteric drainage of pancreatic exocrine secretions. The other was delivery of the pancreas venous effluent to the host portal system and then directly to the hepatic allograft. © 2007 AASLD

Alessiani

Calne

Cecka

Farrell

Groth

Lillehei

Petruzzo

Philosophe

Pirenne

Starzl

Stratta

Sutherland

Thai

Young

English

PubMed

Crossref

World's longest surviving liver-pancreas recipient

Harary, AM

Abu-Elmagd, K

Thai, N

Shapiro, R

Todo, S

Fung, JJ

Starzl, TE

Name not available

Abu-Eimagd, K

D-Scholarship@Pitt

Fu I tapraid5/zI1-liver/zll-liver/zlto0807/zlt1331d07g I sangreyj I 8=416/5/07 114:50 I Art: 07-007 1 I LIVER TRANSPLANTATION 12:000-000. 2007 World's Longest Surviving Liver-Pancreas Recipient Albert M. Harary,l Kareem Abu-Elmagd,2 Ngoc Thai,2 Ron Shapiro,2 Satoru Todo,2 John J. Fung,2 and Thomas E. Starzl2 1 New York University School of Medicine and Lenox Hill Hospital, New York, NY, and 2 Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA In July 1988, the liver and pancreas of a cadaveric donor were transplanted separately into a man with type 1 diabetes with end-stage chronic hepatitis B virus. Two features of the operation may help explain the patient's current status as the longest-lived liver-pancreas recipient. One was enteric drainage of pancreatic exocrine secretions. The other was delivery of the pancreas venous effluent to the host portal system and then directly to the hepatic allograft. Liver Transpl12:000-000, 2007. © 2007 AASLD. Received January 3, 2007; accepted April 10, 2007. Kidney and pancreas transplants from the same de-ceased donor are frequently used to treat patients with renal failure caused by diabetic nephropathy. In con-trast, combined transplantation of the liver and pan-creas has been limited almost excluSively to nondia-betic reCipients of abdominal multivisceral grafts. Here, we report simultaneous pancreas and liver transplan-tation to a patient with type 1 diabetes mellitus whose unrelated end-stage hepatic disease was chronic hepa-titis B virus (HBV)-associated cirrhosis. The patient is noteworthy because he is the longest surviving liver-pancreas reCipient in the world. 1 The case illustrates some aspects of pancreas transplantation and their re-lation to liver health that have not been fully clarified to the present day. CASE REPORT In 1963, a 15-year-old patient developed acute HBV hepatitis after the incomplete open heart repair of an atrioventricular (AV) defect in his native Poland. At the age of 29 years (and now in New York), he devel-oped type 1 insulin-dependent diabetes mellitus that required treatment for the next 11 years with approx-imately 70 U of insulin per day in diVided doses. Ongoing liver disease was not apparent until 1982. Analysis of a liver biopsy sample showed ,chronic ac-tive hepatitis and macro- and micronodula.r cirrhosis. Esophageal variceal hemorrhages in November 1986 and February 1987 were associated with ascites and hepatic encephalopathy. In May 1988, he had an episode of vibrio vulnificus bacteremia/cellulitis, fol-lowed by bacterial peritonitis from a gram-positive coccus. Further variceal hemorrhages led to his re-ferral to the University of Pittsburgh Medical Center on June 29, 1988. for urgent consideration of liver transplantation. Two days later, hepatic replacement with the liver of a 6-HLA-antigen-mismatched 12-year-old cadaveriC 'do-nor was carried out by means of conventional tech-niques. The pancreas from the same donor was then transplanted below the transverse mesocolon and arte-rialized with a Carrel patch that encompassed the do-nor celiac axis and superior mesenteric artery origins. The Carrel patch was anastomosed to the recipient's infrarenal aorta. Venous outflow from the pancreas was directed into the recipient's superior mesenteric vein via a short interposition graft of donor iliac vein. Exo-crine pancreatic secretions were drained into the recip-ient upper gastrointestinal tract through 2 end-to-side anastomoses: duodeno-duodenostomy at the second AQ: 1 Abbreviations: HBV. hepatitis B virus; AV, atrioventncular. Supported by National Institutes of Health (grant DK29961). and unrestricted gifts from Frank Sarris and Robert Eberly. Address reprint requests to Thomas E. Starzl. MD, PhD. Transplantation Institute. UPMC Montefiore, 7th Floor. South, 3459 Fifth Avenue. Pittsburgh. PA 15213. Telephone: 412-624-0112; FAX: 412-624-0192; E-mail: mangantl@upmc.edu DOl 10.1002/11.21223 Published online in Wiley InterScience (www.interscience.wiley.com). © 2007 American Association for the Study of Liver Diseases. Fl · .......... _ ...... _-------1 tapraid5/zlt-liver/zlt-liver/zltO0807/zlt1331d07g 1 sangreyj 1 8-4 1 6/5/07 114:50 1 Art: 07-007 1 2 HARARY ET AL. Transverse Mesocolon Vein graft Graft SMV ---"'-<±tth-rr-:-:r;-;;fi' Figure 1. Liver-pancreas transplant operation performed on July 1. 1988_ Key features included the interposition of the transverse mesocolon between the 2 separately revascularized organs. delivery of the pancreas graft venous outflow into the host superior mesenteric vein (SMV), and the method of _-teric drainage of pancreatic u:ocrine secretions. With slight modifications (e.g .• double exocrine drai_ge is not neces-sary). the pancreas engraftment technique could be used to test the value of portal pancreatic venous drainage in pancre-as-alone or pancreas-kidney recipients. PV. portal vein; IVC. interior vena cava. part of the host duodenum. and duodeno-jejunostomy near the host ligament of Treitz (Fig. 1). Immunosuppression was with cyclosporine. azathio-prine. and prednisone to which a 14-day course ofba-siliximab and muromonab was added to treat an early rejection. Thirteen weeks after transplantation. an in-crease in serum bilirubin (peak 7.1 mg/dL) and transaminase concentrations (serum glutamic-oxaloa-cetic transferase peak 400 IU) occurred that were first ascribed to rejection. then to recurrent HBV hepatitis. A stable functional state was achieved after 7-8 months. Since then. he has had mild to moderate increases of serum transaminases (usually less than twice normal) but with normal liver synthetic functions and bilirubin concentrations despite slowly worsening biopsy evi-dence of hepatic fibrosis (last sample 2003). He was found to be infected with hepatitis C in 1994 and was unsuccessfully treated with interferon alfa. He was treated with lamivudine between 1997 and 2004. His current medications include 25 mg cyclosporine twice a day (trough levels frequently undetectable). 5 mg/d prednisone. 10 mg/d adefovir dipivoxil, 2 antihyperten-sive drugs. and antacids. Serum creatinine concentra-tions are normal. He has required no insulin therapy since his double organ transplant. His principal medical problems since 1990 have been cardiovascular. for the most part re-lated the incomplete closure of the AV defect at age 15. In 1995, a permanent pacemaker was inserted for the treatment of heart block. Small strokes began in 1997 and were attributed to emboli passing through the in-completely closed AV defect. He then developed pro-gressive congestive heart failure. and a second major cardiac procedure was undertaken in 2001. The oper-ation included definitive repair of the AV septal defect, tricuspid valve annuloplasty, porcine mitral valve re-placement, and a single-vessel coronary artery bypass graft. Glucose homeostasis has been excellent through-out. Current liver functions include a normal bilirubin (0.5 g/dLJ, aspartate aminotransferase (38 IUl, serum albumin (4.1 g/dL), and international normalization ra-tio (1.2). The patient has been able to work. continues to demonstrate a sharp and ironic wit, and remains an avid reader of history books. DISCUSSION When the operation for this patient was planned in 1988. liver transplantation under cyclosR0rine-based immunosuppression had become a widely accepted form of treatment. 2 In contrast, pancreas transplanta-tion faced an uncertain future because of its excessive morbidity and mortality. 3 One problem was that neither the whole organ pancreas transplantation Originally de-scribed by Lillehei et al.,4 nor the then more popular option of partial (segmental) pancreatic transplanta-tion, were standardized operations. The principal lethal risks with both kinds of procedure were associated with enteric drainage of the graft exocrine secretions. Con-sequently. the strategy with almost all pancreas trans-plantations from the early 1970s to the mid-1980s was to divert the secretions to extra-alimentary destinations (e.g .• the host urinary tract or free peritoneal cavity) or to eliminate the secretions by blocking the ducts of segmental pancreas grafts (e.g.. with polymer injec-tion).3.5 In opposition to these trends. we had urged the use of the whole pancreas with enteral drainage of its exocrine secretions via the graft duodenum. 6 Both of these recommendations were carried out in our 1988 liver-pancreas reCipient with diabetes (Fig. 1). A second technical question was where to direct the venous outflow of the pancreas allograft. With the pelvic implantation site that remains in common use today for patients with diabetes who do not have liver disease. the pancreatic venous effluent usually is directed into the host systemiC circulation by anastomosis to an iliac vein or to the inferior vena cava. This practice has po-tentially important undesirable implications. Glucose homeostasis is maintained by the liver. where insulin is almost completely removed from the blood with a single transhepatic passage. However. the insulin binding has LIVER TRANSPLANTATION. DOl lO.lO02/lt. Published on behalf of the American Association for the Study of Liver Diseases AQ:2 1 tapraid5/zlt-liver/zlt-liver/zltO0807/zlt1331d07g 1 sangreyj 1 S=4 1 6/5/07 114:50 1 Art: 07-0071 many other consequences for the liver. In the 1970s, it was shown that the first pass-exposure of the liver to endogenous or portally infused insulin is critical for normal maintenance of hepatic size, ultrastructure, function, and the capacity for regeneration. 7-11 To con-fer the hepatotrophic benefits of insulin and other mol-ecules from the pancreas on the cotransplanted liver of our 1988 recipient, the venous effluent ofthe pancreas graft was drained into the host superior mesenteric vein. Thus. the operation carried out in 1988 differed greatly from the only previous liver-pancreas trans-plantation into a patient with diabetes. In the earlier case (October 3, 1979), Calne et al. 12 implanted a seg-mental pancreas graft (body and tail) from the same donor in the pelvis of a liver recipient after polymer injection of the duct system. Venous outflow was di-rected into the iliac vein. Glucose homeostasis was promptly normalized. The reCipient required resump-tion of insulin after 1 year, but survived for 6.1 years. No other diabetic liver reCipients are known to have undergone the double organ transplantation until the 1988 patient reported here. However. an en bloc allograft of the liver and pan-creas (with the attached duodenum) was being used in Pittsburgh throughout the 1988-89 period as replace-ment for the resected native upper abdominal organs of patients without diabetes with hepatic, pancreatic, or duodenal malignancies that had metastasized region-ally.13 A total of 21 patients received these composite ("cluster") allografts. Despite a high rate of tumor recur-rence, the 3- to 5-year survival was >30%. All of the 21 recipients became insulin independent and remained so up to the time of death or to the 3- to 5-year follow- . Up.14 However, graft pancreatitis was a frequent early complication and caused one death. 13.14 Because of the possibility that pancreas complica-tions could jeopardize the liver graft, the 2 organs were separated and transplanted individually in our 1988 patient with diabetes, above and below the host trans-verse mesocolon. This concern notwithstanding. recent reports of pancreas transplantation in 3 liver recipients with diabetes, 2 in Brussels15 and 1 in Leeds,16 have revitalized interest in the original en bloc transplant operation. Both groups emphasized the advantages (in-cluding the safety) of the en bloc procedure while noting the scarcity of liver recipients with diabetes who had undergone simultaneous pancreas transplantation of any kind « 10 reported). In view ofthe small number of reported cases, it is possible that pancreas transplan-tation is being underused in liver reCipients with diabe-tes. Our policy when pancreas transplantation is used in a liver reCipient. whether Simultaneously or later. has been to route the pancreas venous drainage through the hepatic allograft because this provides an ideal met-abolic environment for the new liver. 17 In turn, survival of the pancreas may be aided by the well-known im-mune protective effect of the liver. 18 The perSistence for 18 years of the still well-functioning liver allograft re-ported here was of particular interest in view of its PERSPECTIVES IN LT 3 prompt infection by HBV. and later hepatitis C virus. Although the HBV infection was treated with hyperim-munoglobulin, this therapy was not standardized in 1988. and effective antiviral drugs were not yet avail-able. Consequently, the prognosis for disease recur-rence was so dismal that HBV was considered at the time to be a relative contraindication for liver transplan-tation by most insurance carriers and an absolute one by all government agenCies that funded this procedure. This patient beat the odds because of new HBV thera-peutic developments that have continued to the present time. Although the foregoing anatomic/metabolic consid-erations have been focused on the welfare of the hepatic allografts. they could be relevant to the health of native livers of reCipients with diabetes in whom the allograft pancreas has been transplanted alone or in combina-tion with the kidney or other nonhepatic organs. More than 90% of such pancreas grafts have their venous effluent diverted into the systemic circulation (i.e .. around the liver). 5 The non physiologic drainage results in systemic hyperinsulinemia and has been associated with dyslipidemia, accelerated atherosclerosis. and in-sulin resistance. 19 In turn, insulin resistance is of par-ticular concern to hepatologists because it is thought to be a seminal factor in pre- and posttransplantation nonalcoholic steatohepatitis syndromes.2o Formal comparisons of portal vs. systemic venous drainage in pancreas alone and kidney-p~creas reCip-ients 19.21.22 have not included assessment of the effects on the liver. At the 40th armiversary celebration of the first human pancreas transplantation held at the Uni-versity of Minnesota during December 6-8, 2006, inter-est was expressed in carrying out studies that would bring this important question to closure. REFERENCES 1. Cecka JM. Terasaki PI. World transplant records. In: Clin-ical Transplants 2001. Los Angeles: UCLA Immunogenet-ics Center; 2005:391 2. National Institutes of Health Consensus Development Conference on Liver Transplantation. Sponsored by the National Institute of Arthritis. Diabetes, and Digestive and Kidney Diseases and the National Institutes of Health Of-fice of Medical Applications of Research. Hepatology 1984; 4(1 Suppl):I5-110S. 3. Groth CG. ed. In: Pancreatic Transplantation. Philadel-phia. PA: WE Saunders; 1988Ll-413. 4. Lillehei RC. Simmons RL. Najarian JS. Wei! R. Uchida H. Ruiz JO, et al, Pancreatico-duodenal allotransplantation: experimental and clinical experience (includes discussion from the floor). Ann Surg 1970: 172:405-436. 5. Sutherland DE. Gruessner RW, Dunn DL, Matas AJ, Hu-mar A. Kandaswamy R. et al. Lessons learned from more than 1.000 pancreas transplants at a single institution. Ann Surg 2001;233:463-501 6. Starzl TE. Iwatsuki S. Shaw BW Jr, Greene DA, Van Thiel DH, Nalesnik MA. et al. Pancreaticoduodenal transplanta-tion in humans. Surg Gynecol Obstet 1984:159:265-272. 7. Starzl TE, Francavilla A. Halgrimson CG. Francavilla FR. Porter KA, Brown TH. et al. The origin. hormonal nature, and action of hepatotrophic substances in portal venous blood. Surg Gynecol Obstet 1973:137:179-199. LIVER TRANSPLANTATION. DOl 10. 1002 lIt. Published on behalf oj the American AssociationJor the Study oj Liver Diseases 1 tapraid5/zlt-liver/zlt-liver/zlto0807/zlt1331 d07g 1 sangreyj 1 5=4 1 6/5/07 114:50 1 Art: 07-007 1 4 HARARY ET AL. 8. Starzl TE. Lee !Y. Porter KA, Putnam CW, The influence of portal blood upon lipid metabolism in normal and diabetic dogs and baboons, Surg Gynecol Obstet 1975;140:381-396. 9. Starzl TE. Porter KA. Kashiwagi N. Lee !y, Russell WJI. Putnam CWo The effect of diabetes mellitus on portal blood hepatotrophic factors in dogs. Surg Gynecol Obstet 1975; 140:549-562. 10. Starzl TE. Porter KA. Kashiwagi N. Putnam CWo Portal hepatotrophic factors. diabetes mellitus and acute liver atrophy. hypertrophy and regeneration. Surg Gynecol Ob-stet 1975;141:843-858. 11. Starzl TE. Watanabe K. Porter KA. Putnam CWo Effects of insulin. glucagon. and insulin/glucagon infusions on liver morphology and cell division after complete portacaval shunt in dogs. Lancet 1976:1(7964):821-825. 12. Calne RY. Rolles K. White DJG. Thiru S. Evans DB. McMas-ter p, et al. Cyclosporin A initially as the only immunosup-pressant in 34 recipients of cadaveric organs: 32 kidneys. 2 pancreases. and 2 livers. Lancet 1979:2: 1033-1036. 13. Starzl TE. Todo S. Tzakis A. Podesta L. Mieles L. Demetris A. et al. Abdominal organ cluster transplantation for the treatment of upper abdominal malignancies. Ann Surg 1989:210:374-386. 14. Alessiani M. Tzakis A. Todo S. Demetris AJ. Fung JJ. Starzl TE. Assessment of 5-year experience with abdomi-nal organ cluster transplantation. J Am Coll Surg 1995; 180:1-9. 15. Pirenne J. Deloose K. Coosemans W. Aerts R. Van Gelder F. Kuypers D. et al. Combined "en bloc" liver and pancreas transplantation in patients with liver disease and type I diabetes mellitus. Am J Transplant 2004:4:1921-1927. 16. YoungAL. Peters CJ. Toogood GJ. Davies HM. Millson CEo Lodge JPA. et al. A combined liver-pancreas en-bloc trans-plant in a patient with cystic fibrosis. Transplantation 2005:80:605-607. 17. Thai NL. Abu-Elmagd K. Khan A. Bond G, Basu A. Torn K. et aI. Pancreatic transplantation at the University of Pitts-burgh. In: Cecka JM, Terasaki PI, eds. Clinical Trans-plants 2004. Los Angeles. CA: UCLA Tissue Typing labo-ratory; 2004:205-214 18. Starzl TE, Demetris AI. Trucco M. Murase N. Ricordi C. Ildstad S, et al. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993;17:1127-1152. 19, Stratta RJ. Shokouh-Amiri MH. Egidi F. Grewal HP. Kizi-isk T. Nezakatgoo N. et al. A prospective comparison of simultaneous kidney-pancreas transplantation with sys-temic-enteric versus portal-enteric drainage. Ann Surg 2001 :233: 740-751. 20. Farrell GC. Larier CZ. Nonalcoholic fatty liver disease: from steatosis to Cirrhosis. Hepatology 2006;43(2 Suppl 1):599-5112. 21. Philosophe B. Farney AC, Schweizter EJ. Colonna JO. Jarrel BE, Krishnamurthi V. Superiority of portal venous drainage over systemic venous drainage in pancreas transplantation: a retrospective study. Ann Surg 2001; 234:689-696. 22. PetruzZQ P. Da Silva M, Feitosa LC. Dawwahra M, Lefran-cios N. Dubemard JM. et al. 5imultanous pancreas-kid-ney transplantation: portal venous systemiC venous drainage of the pancreas allografts. Clin Transplantation 2000;14:287-291. LIVER TRANSPLANTATION. DOl 1O.1002/lt. Published on behalf of the American Associationfor the Study of Liuer Diseases 

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World's longest surviving liver-pancreas recipient

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