Themes of liver transplantation

Abstract

Liver transplantation was the product of five interlocking themes. These began in 1958-1959 with canine studies of then theoretical hepatotrophic molecules in portal venous blood (Theme I) and with the contemporaneous parallel development of liver and multivisceral transplant models (Theme II). Further Theme I investigations showed that insulin was the principal, although not the only, portal hepatotrophic factor. In addition to resolving long-standing controversies about the pathophysiology of portacaval shunt, the hepatotrophic studies blazed new trails in the regulation of liver size, function, and regeneration. They also targeted inborn metabolic errors (e.g., familial hyperlipoproteinemia) whose palliation by portal diversion presaged definitive correction with liver replacement. Clinical use of the Theme II transplant models depended on multiple drug immunosuppression (Theme III, Immunology), guided by an empirical algorithm of pattern recognition and therapeutic response. Successful liver replacement was first accomplished in 1967 with azathioprine, prednisone, and antilymphoid globulin. With this regimen, the world's longest surviving liver recipient is now 40 years postoperative. Incremental improvements in survival outcome occurred (Theme IV) when azathioprine was replaced by cyclosporine (1979), which was replaced in turn by tacrolimus (1989). However, the biologic meaning of alloengraftment remained enigmatic until multilineage donor leukocyte microchimerism was discovered in 1992 in long-surviving organ recipients. Seminal mechanisms were then identified (clonal exhaustion-deletion and immune ignorance) that linked organ engraftment and the acquired tolerance of bone marrow transplantation and eventually clarified the relationship of transplantation immunology to the immunology of infections, neoplasms, and autoimmune disorders. With this insight, better strategies of immunosuppression have evolved. As liver and other kinds of organ transplantation became accepted as healthcare standards, the ethical, legal, equity, and the other humanism issues of Theme V have been resolved less conclusively than the medical-scientific problems of Themes I-IV.

Figure 1

Auxiliary liver homotransplantation in dogs (the Welch procedure). Note that the portal venous inflow of the extra liver is from the inferior vena caval bed while the native liver retains a normal blood supply. It was suspected from the beginning that this was a major flaw in the design of the procedure. From: Ann Surg 160:411-439, 1964.

Figure 2

Complete liver replacement in the dog circa 1958-9. The fact that this was a canine rather than a human operation is evident only from the small multiple lobes of the allograft and the biliary drainage with cholecystoduodenostomy. In my first report (3), an “outflow block” syndrome resembling endotoxin shock was described if donor body weight was less than half that of the recipient (one cause of today’s “small for size” syndrome).

Figure 3

Bottom Center: Multivisceral allograft transplanted in dogs in 1959 (6,7) and in humans for the first time 3 decades later (46). With removal of different organs from the common vascular stem, this original procedure has had many subsequent variations. Lower Left: Liver-intestinal transplantation (47,62). Top Middle: Cluster of upper abdominal organs (55). Right: Mid gut organs except the liver. From: Liver Transplant & Surg 4:1-14, 1998.

Figure 4

The double liver models that led to progressively precise identification of the hepatotrophic factors that influenced liver size, ultrastructure, function, and the capacity for regeneration: (A) Welch’s index operation of auxiliary liver allotransplantation (see also Figure 1); (B) non-transplant split liver model that differentiated the effect on the liver of systemic venous (vena caval) versus splanchnic (portal) blood; (C) separation with the double liver fragment model of the qualities of venous blood from the upper and lower abdominal viscera; and (D) selective infusion of candidate hepatotrophic molecules into one or the other of 2 liver fragments, both of which had an arterial supply only. From: Liver Transplant & Surg 4:1-14, 1998.

Figure 5

The dramatic effect of portacaval shunt on serum cholesterol concentration in a child with homozygous familial hyperlipoproteinemia. These observations (24) and canine studies of lipid synthesis with the models shown in Figure 4 (25) suggested that the liver was the principal site of cholesterol homeostasis. Although we considered familial hyperlipoproteinemia to be a candidate disease for liver replacement from the mid 1970s, this was not accomplished until February 14, 1984 (44,45) by which time more evidence that this was an appropriate step was obtained in New York, Bethesda, and Dallas. Interactions over more than a dozen years between experts in cholesterol metabolism in these cities and the author (TES) are described in the chapter “The Little Drummer Girls” of The Puzzle People (128). From: Lancet 2:940-944, 1973

Figure 6

The first 3 human recipients with prolonged survival following liver replacement in July and August, 1967. The adult, Carl Groth, was a Swedish surgeon-in-training whose tenures in Denver as a Fulbright Scholar (1966-68) and faculty member (1970-71) were near the beginning of his Olympian career. After returning to Stockholm to occupy a Chair in transplantation surgery created for him at the Karolinska Institute, Groth developed the multiorgan transplant program that produced the first liver transplantations in Sweden. His numerous honors include the King’s Medal of his country and the Medawar Prize, the highest distinction of the international Transplantation Society.

Figure 7

World’s longest surviving liver recipient whose 40^th post-transplant anniversary will take place January 22, 2010. The primary disease diagnosis was biliary atresia, but the right lobe of her excised liver contained an incidental 2.7 × 1.8 centimeter hepatoma. The serum alpha fetoprotein level was 6 mg/cm at one post-transplant month, trace-present at 4 months, and undetectable since (Ref 189). The patient’s companion, now a retired United States Marine, is her husband of many years. The statue behind them is Roberto Clemente (1934–1972), the greatest baseball right fielder of all time who was killed bringing food by air flight to victims of the catastrophic Nicaraguan earthquake.

Figure 8

David Van Thiel (1941-), gastroenterologist-hepatologist without whose herculean efforts, the University of Pittsburgh liver transplantation program could not have been established.

Figure 9

The cell migration and localization of organ and bone marrow cell transplantation. Organs (here a liver) are composites of architecturally fixed cells and mobile multilineage cells of bone marrow origin (“passenger leukocytes”) that include pluripotent hematolymphopoietic stem cells (157-159). Within minutes after organ transplantation, the passenger leukocytes simulate a bone marrow cell infusion by migrating selectively to recipient lymphoid organs where they induce the depleted antidonor T cell response. Although the clonal response normally destroys the invading donor cells and their outlying source organ (rejection), the response may be exhausted and deleted if it is too weak to eliminate the invading donor cells during the first few weeks of maximal cell migration. Perpetuation thereafter of survival of the bystander organ allograft requires persistence of enough donor leukocytes to maintain the initial exhaustion-deletion. Importantly, the invading donor cells are immune competent and their response against the recipient also must be exhausted and deleted for a successful transplant outcome (see Figure 10).

Figure 10

The kinetics of immunosuppression-aided exhaustion and deletion of the contemporaneous host versus graft (HVG, upright curve) and graft versus host (GVH, inverted curve) responses in organ recipients following the cell migration shown in Figure 8. Although HVG is the dominant response in most organ recipients (expressed as rejection), serious or lethal GVH reactions (expressed as graft versus host disease [GVHD]) are not rare in recipients of lymphoid-rich organs (liver, intestine). In naturally immune deficient or cytoablated bone marrow cell recipients, GVHD is avoided by using histocompatible (HLA-matched) donors. Therapeutic failure after either organ or bone marrow cell transplantation implies the inability to control one, the other, or both of the responses. From New Engl J Med 339:1905-1913, 1998.

Figure 11

The many faces of transplantation tolerance. Outer Circle: The continuum of experimental and clinical donor leukocyte chimerism-associated tolerance models that can be traced back to observations in 1945 in freemartin cattle (upper left) whose fused placentas permitted fetal cross-circulation, blood chimerism, and reciprocal immune nonreactivity. Inner Graphic: Permutations of tolerance defined as balances between persisting migratory donor leukocytes and the number of antidonor T cells undergoing steady state exhaustion-deletion. The achievement of balances and the resulting clinical phenotypes are influenced by the dose, type, and timing of immunosuppressive therapy and by the dose, type, timing, route, and localization of the migrant donor cells. The single most important factor leading to the macrochimerism of bone marrow cell transplantation versus the microchimerism of most organ (and composite tissue) recipients is enfeeblement of recipient immune reactivity before the arrival of donor cells in the first instance and after their arrival in the second. The non-specific potential “stabilizing factors” in the left-directed arrow above the human silhouette include special cells (e.g. T-regulatory), enhancing antibodies, graft secretions, and endogenous cytoprotective molecules.