cases within zo or 30 minutes after portal revasc1 ~Ay_un:;ut:aysensitive others in which bleeding disrupts the desired routine, the organs-but which also ensures (when in can be many hours. parenchymal ischemic injury. For example, As described earlier, with the preservation techniques that were of canine kidneys, Ueda and associates have demon- clinical use through 1987, the safe preservation limits for human with a microphil technique the remarkable "pruning" of the ers were set at 6 to 8 hours. These limits were conservative since arteries and arterioles that can occur within 60 minutes af- livers could be stored for two or three times this interval after restoration of the renal arterial supply of inadequately preserved 167 sion with oncotically controlled electrolyte (Collins') solutions with A devascularization is the consequence that is far less ex high potassium concentration 36 or with a plasma-like solution in kidneys preserved with UW solution than in kidneys pre When the potassium-rich Euro-Collins solution was used to with the Euro-Collins solution (Fig 39). human livers for 3 to 8 hours, there was no correlation at all The sinusoidal endothelium of the liver is a unique microcircula tween liver injury and preservation time as judged by a battery bed. It lacks a well-defined basement membrane, is structurally liver function tests.52'53 Makowka and associates 161 and Miller cialized, forming large fenestrae to allow exchange of metabo colleagues162 made the additional perplexing observation that between the blood and hepatocytes, and is in close proximity to 168 condition of the donor was not important in influencing the Kupffer cells. The cell swelling and subsequent damage that come. Seemingly "unsatisfactory" cadaveric donors with poor bloo during hypothermia are thought to be responsible for the fa gases, an unstable cardiodynamic state, or even moderately areas of sinusoidal lining cell denudation observed ultrastructur mal hepatic function tests provided livers that performed as well after cold preservation. organs removed from ideal donors. The same thing has been Destruction of the liver that occurs after reimplantation by the ported from the European liver registry.163 reperfusion" mechanism is thought to be caused by two different 159169 The fact that liver injury as judged by hepatic function tests, interrelated events. ' In the first, loss of the sinusoidal lining well as graft and patient survival, has not had a significant associa-:' cells disrupts the architectural framework of the hepatic microvas tion with preservation time does not mean that long storage culature, preventing adequate restitution of the blood flow. Instead 61 should be ~cceptedlightly. Even with the UW solution/ very of the antithrombogenic environment normally present in the sinu icant deterioration of graft quality has been demonstrated in soids, exposure of the blood to coagulation stimulants results in fi trolled canine experiments between 1 and 24 hours of preserv:1 brinogen activation and local clotting with trapping of red blood Apparently, undefined factors in the heterogeneous human cells and leukocytes.159' 169 This contributes to the circulatory block and recipient population are important enough to obscure the ex ade and fosters the accumulation of leukocytes. These cells likely pected time/tissue damage relationship. serve as sources of tissue damaging oxidant (free radical) molecules, At present, the transp1antation itself serves as the test by which which is the second proposed pathway of destruction during reper the assessment of ischemic injury is made after the fact instead fusion injury. prospectively. Intracellular pH, energy charge, mitochondrial func Protocol biopsies of human liver allografts obtained during back tion, and surrogate or direct measures of oxygen free-radical species table preparation and 1 to Z hours after revascularization in the re in preserved liver tissue do not accurately predict graft quality in ex cipients have detailed the sequential histologic events that occur af perimental animals.164' 165 Instead, the ATP content of the preserved ter reperfusion.169 As would be expected, the vast majority of back graft falls sharply even during the initial chilling infusion. Because it table biopsy specimens are essentially normal by light microscopic is the rapidity of ATP restoration after revascularization rather than examination except for hydropic cell swelling. Sinusoidal lining cell its level before reperfusion that is discriminating as a prognostic integrity cannot be reliably evaluated on immersion-fixed, paraffin sign, ATP measurements during preservation have not been thought embedded, and routinely stained sections. However, ultrastructural to be helpful prospectively, with the exception of a single clinical re examination ofthe same biopsy specimens may show severe sinusoi port.166 dal lining cell damage and denudation (Fig 40) like the changes ob It may be that none of these metabolic tests are appropriate since served in animals.156- 159 However, no specific histologic feature on they all reflect hepatocyte metabolism. This would seem logical the back-table biopsy specimen is able to predict postoperative or-
50 51 FIG 40. A, plastic-embedded sections of donor livers reveals that the sinusoidal lining cells bear the brunt of cold preservation injury. Note the endothelial cell denudation (arrows) with foss of the space of Disse. Hepatocytes usually show mild reversible changes such as a FIG 39. vacuolization and bleb formation (arrowhead). B, ultrastructural analysis confirms the Dissecting photomicrographs of renal vascular architectures filled with silicon rubber of sinusoidal endothelial cells, and leukocytes become directly adherent to hepato pound 1 hour after reperfusion of the grafts 40). A, 72-hour Euro-Collins group. (x cytes (EL =endothelial cell; L =lymphocyte; N = neutrophil; H = hepatocyte) (From Kak complete filling defect of subcapsular cortex and medulla. Patchy distribution of a izoe S, Yanaga K, Starzl TE, et al: Hepato/ogy [in press). Used by permission.) lar area, irregular and deformed pattern of interlobular artery and glomerulus can be seen, B, 72-hour UW group. The capillary networks of both cortex and medulla are fully function those preclude organ use (see earlier with silicon rubber. (From Ueda Y, Todo S, lmventarza 0, et al: Transplantation 1989; other than that 48:913-918. Used by permission.) discussion). Within hours after reperfusion, livers that were minimally dam aged during preservation show surprisingly few pathologic alter ations. By contrast, zonal coagulative hepatocellular necrosis, either in ·the perivenular or periJ?ortal regions, accompanied by· a brisk neutrophilic exudate, and acidophilic bodies scattered throughout the lobule are signs of serious graft injury and harbingers of poor postoperative function in many instances (Fig 41). The evaluation of postperfusion injury can be influenced by the site of biopsy. It must be remembered that core needle biopsy specimens taken from the periphery of the organ may show more severe injury than the deeper parenchyma, and as always, the pathology findings should be interpreted in context with the complete clinical profile. Once the liver is revascularized, quick assessment of its quality from metabolic studies is far more practical than a postperfusion biopsy. Measurements of blood amino acids clearance and study of other products of intermediary metabolism have been used to distinguish those patients whose new livers can and cannot 170 173 be expected to recover. - However, one of the simplest of all signs, namely, bile production by the new liver, has long been recognized as the most important predictor of success after revas 174 175 176 cularization. Recent studies in animals ' and humans have shown an almost perfect correlation between bile production, rapidity of restoration of liver ATP levels after revascularization, survival. Next to bile production by the graft, restoration of good clotting 95 101 116 170 171 the recipient - and absence of lactic acidosis ' ' are dictors of success. The coagulopathies that occur during liver transplantation are characterized by fibrinolysis, defi ciencies of specific clotting factors and platelets, and consumption
FIG 41. Zonal hepatocellular necrosis in a reperfusion biopsy, particularly when periportal in A, in the first few weeks after transplantation, grafts with mild ischemic injury show centri bution (arrows), is a harbinger of poor postoperative function in many cases (PT = lobular hepatocyte swelling and hepatocanalicular cholestasis (PT = portal tract; CV = tract; CV = central vein). (From Kakizoe S, Yanaga K, Starzl TE, .et al: Hepatology [in central vein). B, when t~einitial injury is more severe or periportal in distribution, cholang press]. Used by permission.) iolar proliferation and acute c,holangiolitis are seem and represent attempts at repair, cases;)$/SUGC\'lSStul (see text), c::;,thi'J. structural. changes and cholangiolar clotting. IMMUNE EVENTS Even organs severely damaged from preservation have the to completely recover after transplantation, both functionally structurally. Biopsy specimens are often obtained at intervals or weekly during the first 1 or 2 months in such because clinically they can develop a prolonged cholestatic drome that does not resolve with increased immunosup 144 179 If other explanations for primary nonfunction or dysfunction of therapy. ' A fairly ordered sequence of events may be seen liver graft have been exhausted, host immune factors may be re such specimens. 180 181 ;1-Junsible. It is well known that human kidney ' and heart The histologic evolution of repair depends on the degree of 144 145 184 can be destroyed almost immediately by humoral anti- struction. ' If the initial damage was relatively mild, lobular in a.process called hyperacute rejection. There have been no generation, as evidenced by hepatocellular mitoses and twinning 1nP.dUivocal examples of hyperacute rejection after clinical hepatic the plates, starts 2 to 3 days after transplant and is complete by 7 supporting the widely held opinion that the liver is 10 days. Mild perivenular hepatocanalicular cholestasis and to this kind of antibody mediated injury. Because of this re swelling are also common features (Fig 42). If the damage is sistance, liver transplantation has often been performed in spite of and particularly if it is periportal in nature, florid cholangiolar 185 189 tive cytotoxic crossmatches against the donor - and in spite eration ensues, which is invariably accompanied by neutrophils (i.e., 90 193 of ABO incompatibilities/ - which because of the antigraft spec cholangiolitis) and the hepatocellular regenerative changes men ificities of the ABO isoagglutinins would preclude renal or cardiac tioned earlier. These biopsy specimens are also marked by extensive transplantation. Although the liver is resistant to humoral rejection, cholestasis, both hepatocanalicular and cholangiolar, simulating it is probable that humoral antibodies can cause severe graft damage large duct obstruction (see Fig 42). Total or near~total restitution of the liver is the usual outcome if the patient is well enough otherwise in humans. to permit the liver time enough to recover; this may take up to 2 144 145 months. ' For the pathologist, the major differential diagnoses for the find WITH ABO-COMPATIBLE DONORS ings associated with preseiVation injury include large bile duct ob The role and importance of cytotoxic antilymphocyte antibodies struction, sepsis, and hyperalimentation-induced injury. The histo in causing nonfunction of liver grafts are not well delineated. These logic features used to rule out duct obstruction are reviewed in the antibodies with antigraft specificity in kidney recipients are highly section on biliary tract obstruction. Sepsis may be virtually impossi predictive of hyperacute rejection, particularly if the antibody is of ble to separate with certainty. Finally, coexistent rejection is not un the "warm" IgG variety.194 The central event of hyperacute rejection common in these patients and is recognized pathologically by the of the kidney is occlusion of the graft microvasculature by195 rapidly198 appearance of a predominantly mononuclear portal infiltrate with sequestered formed blood elements and by clotting factors. - A evidence of venous endothelial and bile duct damage (see the dis striking feature of hyperacute renal rejection if this does not go cussion of acute rejection pathology). promptly to completion can be the development of a consumption 196 197 199 200 coagulopathy and, sometimes, fibrinolysis. • • • The association of hyperacute kidney rejection with cytotoxic an- tibodies directed against donor lymphocytes was first described by Terasaki and associates180 and confirmed by Kissmeyer-Nielsen and co-workers.181 At first, the simplistic view was that the cytotoxic an tibodies themselves were directly responsible for injuring the endo thelium of the microvasculature. However, it was soon realized that the process was far more complex, that the end result resembled the 57 56 ::..up ...... '""' ...J ------trt the hepatic artery and exclu- tookpH1ee t;ll.rough the action of m~ruam and biliary tree. Occlusion of this tle was known about soluble mediators of the inflammatory limited form of graft injury (biliary) sponse, and most of these biologically potent substances had not m:ay than total organ failure. been discovered. The possible role of these mediators in hyperact lymphocytotoxic antibodies present in human or animal re- humoral rejections has been summarized from a modem perspec of liver grafts disappear from the serum shortly after liver tive by Makowka and colleagues,201 and in a following section, a pos 214 .214· 215· 217•219 In fact, Houssin and associates quite ele sible additional association of these mediators with recipient endo demonstrated in rats that prior liver allografting is able to pro- toxemia will be mentioned. extrahepatic (heart) grafts from undergoing hyperacute rejec Hyperacute rejection of the liver was suspected after one of the .214-216 Both a strong donor-specific and weaker nonspecific first clinical attempts of orthotopic liver transplantation in a child party protective effect is seen.214- 216 Fung and colleagues have whose graft developed hemorrhagic necrosis a few hours postoper that liver allografts can protect kidney allografts from the atively.202 The gross description of this liver was similar to the find 203 204 donors in presensitized humans and prevent hyperacute re- ings described many years later in rats and in rhesus monkeys 1.217 They documented the disappearance of donor"specific sensitized with skin homografts and blood transfusions before or class I lymphocytotoxic antibodies from the recipient circula thotopic liver transplantation. However, experiments in rodents have shortly after transplantation. 217'219 However, this protective ef also demonstrated the difficulty of inducing intense enough sensiti 203204 205206 is not always seen and can be overridden in animals ' and zation to reduce hepatic graft survival ' or else have shown that "u".;ibly humans. 184'208 In animals, it was noted that intense sensiti liver heterografts are rejected by heterospecific antibodies later and 203204 206207 protocols are required to overcome this effect. ' In hu less violently than the heart and presumably other organs. · at least two recipients have hyperacutely rejected kidney Such is the resistance of the liver to cytotoxic antibodies that a after they had received liver allografts from the same donor positive cytotoxic crossmatch should not preclude an effort at liver than 1 day prior.208 These cases have served as prototypes for transplantation. It also is becoming evident that accelerated (possi 208 210 recognition of antibody-mediated rejection in the liver. bly humoral) rejection of liver grafts can occur. - However, the It is known that human and rat livers secrete soluble (class I MHC) process develops more slowly than with the kidney and presumably antigens that presumably bind to and neutralize the circulating an other organs, it may be reversible, and it is not strongly associated tibodies.211-213 Gugenheim and co-workers have also shown in rats with the antigraft antibodies that are being measured in routine typ 208 donor specific absorption or binding of the lymphocytotoxic anti ing laboratories. A progressive and severe coagulopathy develop bodies and donor-specific cytotoxic T lymphocyte (CTL) by non ing shortly after hepatic revascularization should arouse suspicion parenchymal cells of the liver.215' 216 Kupffer cell blockade sup of an accelerated rejection, even if there has not been a positive cy 208 presses this protective effect. It also appears that Kupffer's cells may totoxic antibody crossmatch. be involved in the neutralization of lymphocytotoxic antibodies in The resistance of the liver to hyperacute rejection from lymphocy humans/ 69' 218 either directly or indirectly, by binding immune com totoxic antibodies is thought to be the result of several factors. The plexes. Therefore, the liver probably acts as a "sink" for the deposi most important of these may be the dual afferent blood supply, a si tion of the lymphocytoxic antibodies, immune complexes, and per nusoidal network coated with Kupffer's cells rather than a capillary 168 haps CTLs. Whether this deposition is toxic or not may depend on microvasculature, secretion of soluble major histocompatibility the antibody class and titer and on the activity of the Kupffer cells at complex (MHC) antigens into the circulation,211- 213 and nontoxic absorption of alloantibodies or immune complexes by the Kupffer the time of challenge. 169214 219 Knechtle and associates have recently shown that hyperimmu- cells. ' - The liver receives an afferent blood supply from both nized rats hyperacutely reject livers within hours after transplanta the hepatic artery and portal vein, and compromise to 'either results tion.203 Rat transplantation may not be the ideal model to study this in compensatory flow in the other, presumably protecting the liver 168 phenomenon since, in most instances, no attempt is made to recon from ischemic injury. Most of the microvasculature network of the struct the arterial supply. Gubernatis and colleagues were able to liver is sinusoidal, which is lined by widely spaced (fenestrated) en 68 demonstrate early antibody-mediated rejection in presensitized dothelium with no underlying basement membrane? In contrast, rhesus monkeys.204 The sensitized animals rejected the livers at an both the heart and kidney have an arterial end organ blood supply 59 58 an 5 ----- .. ~.. ...,~uuu1mdeposits, arteritis,~and ischemic ne,-. ....-.o~ typical of that seen with hYPeracute rejection of other organs. 221 ever, an extreme level of presensitization was required (multiple bgressiOn of findings (Fig 43*). grafts and donor blood transfusions), which may not reflect reperfusion show prominent red clinical situations where a positive lymphocytotoxic crossmatch sludgihg, clustering of neutrophils, and fibrin deposition encountered. Furthermore, the antibodies apparently causing sinusoids. Focal hemorrhage into the space of Disse, hepato cytoaggregation, and single-cell acidophilic necrosis then damage in the animal experiments mentioned earlier 03 • 204 were well characterized. Whether this protective effect can be Small clusters of hepatocytes undergoing coagulative necro by high-titer lymphocytotoxic antibodies in humans is not clear cell congestion, and hemorrhage appear in samples taken 1 present. If it does occur, routine lymphocytotoxic crossmatch days later. The areas of necrosis may not demonstrate any par suits are unable to predict the phenomenon beforehand. The zonal distribution. Portal and central veins often shown par apparent correlation between the pretransplant crossmatch degeneration of the wall, with the attachment of a fibrin early postoperative events is a requirement for an increased which extends in a flamelike fashion into the lumen. Ar of platelet and blood transfusions.220 are usually less severely affected than the veins; endothelial hypertrophy, endothelial denudation, and focal fibrin thrombi common findings. Intimal neutrophilic or necrotizing arteritis WITH ABO-INCOMPATIBLE DONORS both) with medial inflammation can be seen on occasion (see Fig . Cholangiolar proliferation as a sign of regeneration is recogniz Although ABO-incompatible liver transplantation can be done 90 193 by 2 to 3 days, and the histologic features at this point may be the event of extreme need/ - the risk is increased. - • • 190 193 221 difficult, if not impossible, to separate from preservation injury. Isoagglutinin fixation has been demonstrated in the microvasc1"~ ·, progressive patchy hemorrhagic infarction of the organ ture of ABO-incompatible liver grafts in a collection of cases which hemorrhagic infarction occurred five times more Immunofluorescence immunoperoxidase staining done dur than with ABO-compatible grafts.221 There have been several and the development of the syndrome will often reveal diffuse sinu case reports of hemorrhagic infarction.193 ' 222 Minor blood group an venous, and arterial deposition of IgG and IgM, Clq, C3, and tibody systems (Lewis) do not appear to influence graft survival. 223 C4 (see Fig 43). However, only focal patchy deposition of Unexpectedly, ABO-identical grafts have done better than ABO-com and C1Q will be detected in the failed organs. This change in patible but nonidentical organs, and 0 recipients did better in both distribution of deposition is presumably because of rapid catab the incompatible and nonidentical situations.190 • 224 of the immune deposits. The prototype of antibody-mediated rejection of the liver is often, A similar clinicopathologic syndrome may occur in ABO-compati but not invariably, encountered when the major ABO blood group 221 situations when no preformed lymphocytotoxic antibodies are barriers are breached. The syndrome that occurs is the liver 208 221 225 present. ' ' It is likely that other immunologic and nonimmu equivalent of "hYPeracute rejection," but in most instances it devel nologic insults are capable of triggering intravascular coagulation ops more slowly than is seen in heart or kidney grafts. The organs and the cascade of events that occur within the liver, which result in initially reperfuse well and produce bile. A change in the color or hemorrhagic necrosis.184 Therefore, a diagnosis of hyperacute or hu consistency may or may not be noted by the operative surgeon be moral rejection in the liver should be based on a complete clinico fore abdominal closure, and difficulty in achieving hemostasis is not pathologic evaluation of a suspicious case, during which other non uncommon. During the first several posttransplant days, the pa 221 immunologic causes of graft failure are reasonably excluded.221 In tients experience a relentless rise in liver injury test results. Angio addition, several other criteria should be fulfilled (Table 2),t includ grams performed to rule out arterial thrombosis may reveal diffuse ing demonstration of a presensitized state in the recipient, consis luminal narrowing, consistent with vascular spasm. Eventually, he patic failure ensues, which is manifest by wound site bleeding and tent light and immunofluorescent microscopic findings, and the encephalopathy, and retransplantation becomes necessary. Appear ance of the organ at the time of reoperation is similar to that of other *Figures 1-42 appear in Part I. 60 tTable 1 appears in Part I.
61 (usually 1-2 weeks
afte~t~ansplant) with no alternative clinical or pathologic explanation 2. Consistent routine light and immunofluorescence microscopic findings 3. Demonstration of a presensitized state in the recipient* 4. Presence of donor-specific antibodies in an eluate from the failed graft 'Not necessarily lymphocytotoxic antibodies de tected in conventional assays.
of donor-specific antibodies in an eluate from the failed Fulfillment of such a "Koch's postulate" for hyperacute rejec may be overly restrictive, since there are antibody systems out the ABO and lymphocytotoxins that have been associated with rejection.183 However, adherence to these criteria will to the predictive value of screening for antibody systems in the
Primary nonfunction of a liver homograft without an obvious ex should suggest that the new organ may have placed into environment that is hostile because of immunologic or perhaps l1v11immunologic factors. The prompt destruction of hepatic retrans in patients whose first liver grafts have been lost for inade explained reasons has been seen in several centers with experience, causing the word of mouth descriptive term "liver " to be applied to such recipients 208 in the absence of an ex for their behavior.
THE QUESTION OF ENDOTOXEMIA
Sequential histopathologic events during antibody-mediated liver allograft rejection. A, im The inability to predict the perioperative outcome after liver trans mediately after reperfusion, RBCs and neutrophils stuff the sinusoids. 8, 1 to 2 days later, plantation with prognostic premonitors such as quality of donor, small clusters of hepatocytes undergo coagulative necrosis, and portal neutrophilia may time of ischemia, and even the presence of antidonor cytotoxic anti be seen (arrow). C, immunoglobulin and complement components are usually detected bodies has led to a search for other factors. Endotoxemia is one of diffusely throughout the hepatic vasculature early in the course of events, as shown here the most interesting of these possible factors. (immunoperoxidase for lgM), but may be harder to find later on. D, partial fibrinoid degen eration of the veins and arteries with intraluminal thrombi are the most characteristic vas Endotoxin is a macromolecular component of the cell wall of cular findings. E, eventual graft failure is due to widespread hemorrhagic necrosis without gram-negative bacteria. Its most specific and active component is 226 much of an inflammatory infiltrate (pt = portal tract; cv = central vein). F, necrotizing and/ lipid A. However, it has been increasingly recognized that protein or neutrophilic arteritis (arrow) can be seen, as illustrated here but is found in a minority of and polysaccharide components of the molecule can influence its cases. (From Demetris AJ, JaffeR, Tzakis A, et al: Am J Patho/1988; Used 227 228 132:489-502. potency and specificity. ' Because gram-negative bacteria are in- by permission.) 62 63 "Ci
u) OJ ~ .so'" '" Interleukin 1 (IL-l) Family of immunoregulator Stimulates mononuclear cytokines produced phagocytes and other cells by monocytes products, etc. Tumor necrosis factor Product of activated Activates macrophages Fever, induces IL-l from mononuclear (cachectin) macro phages production and endothelial cells, cytotoxic to tumor cells, amplifies microvascular coagulation Colony-stimulating factor Heterogenous glycoproteins Induces production by Stimulates proliferation and from macrophages and B macrophages and B differentiation from marrow-derived lymphocytes lymphocytes precursor cells, activates mature macrophages to produce other mediators Interleukin-2 Lymphokine from activated T Complex pathway by Increases antibacteria-l and anntumor lymphocytes stimulation of IL-l and IL-2 activity of macrophages, increases production from expression of Fe receptors, augmen,t: lymphocytes and IL other immune responses, amplifies'; activation of interferon endotoxin effects (?viscious cycle) alpha production+,zza Endorphins Endogenous opioids Unknown, could stimulate Hypotension, analgesia, behavior mononuclear cells changes, immunoregulation (enhancing and suppressing) "Modified from Morrison DC, Ryan JL: Endotoxin and disease mechanisms. Annu Rev Med 1987; 38:417-432. Used by permission. tlnteJferon alpha and beta are induced by endotoxin directly from B lymphocytes and macro phages. lll ~ ::J ~ O":Ylll 0 (]) ::J Endotoxin in Plasma ;:ED"' ~ (]) lll -o - 1\)~ - :::!". ii) (]) 0 3 OJ _-oo::Ja; 0;::; OJ~rounlcn :-:-q;-o iii g: -· -; Q_ -· "' ::J ::J Q)_::Jm· -o :::) o ru ~z-· "'~a.coo8 12..3Qiaroco gsm:;:,c..-..03 ~~~"iiiiif3 -o ~en C3 iSS)> ro-o o ~ a ~ cB ~ ~cnca_..:;:::::o 1\) ~0-oOJlll~ ::r co....., en.._..:;:,=:: ~ ~:f!';:;'~~i'~ ~ __,\,mon.ru- ~ w::J3~;:s 1\) '< cna.-o:Yru~ G) ~~e;EQ.a.m ""'~ .., 1 w 68 ~- -- -·~· ~ ~ ...... lMl!l_;(:;:ffiett Prinlarily with ient endotoxin. However, endotoxin also could adversely affect liver and other organs of brain-dead donors, particularly if these N OF REJECTION victims of severe trauma. 229 In a small group of six cadaveric plasma endotoxin levels in two of the six were abnormally in the 10 to 20 pg!mL range.249 More investigations on the matter donor endotoxin are planned. t the time orthotopic liver transplantation was first studied in 6 and Chicago8 beginning in the summer of 1958, the only technique for immunosuppression was with total body irra . Attempts were made in 1959 to influence rejection by irradi- either the canine liver donors or their recipients with 1,400 rad. approach was helpful, and in fact, recipient irradiation led 100% mortality. The results were so poor that they were not pub until 1962.255 possibility that there was an immune barrier to successful tation of tissues and organs apparently was not part of the of early clinicians or, for that matter, of most basic This realization awaited the classical studies of Medawar rabbit skin grafts.256 Appreciation by Medawar that rejection an immunologic phenomenon made inevitable almost every that followed. The deliberate depression of immunologic reac 257 258 became feasible theoretically when total body irradiation ' adrenal cortical steroids 259 were shown to be immunosuppres . The next great step was the introduction of thiopurine com- 6-mercaptopurine and its imidazole derivative azathioprine, inhibited heterohemagglutinin formation in mice,260 respon to foreign proteins in rats,261 and rejection of skin and renal 262 263 64 265 in rabbits, rats, ' and dogs/ ' respectively. The foregoing laboratory research proved inapplicable to organ re Placement in humans. Complete control of rejection with a single rarely was achieved without lethal side effects in either ani or humans, as exemplified by the historically important trials total body irradiation 266 as well as by early trials with 6-mer 267 271 and azathioprine. - Hopeful signs from the clinical xn"'"""nce through 1962 were footnotes to an otherwise dreary cat of failures. In 1961, Burnet, a Nobel laureate with Medawar 272 preceding year, wrote in the New England Journal of Medicine : Much thought has been given to ways by which tissues or organs not ge and antigenetically identical with the patient might be made to survive and function in the alien environment. On the whole, the present outlook is highly unfavorable to success. . .. 70 71 current "-><1;1I":(::Hatiransplantatiop W~s'pa§s~d•OU for my application to the extrarenal organs. The modem era of plantation was entered when it was realized that azathioprine prednisone had at least additive, and possible synergistic, With the use of living-related donors, renal transplantation IJec."~' overnight a practical means of treating renal failure.273· 274 There only 23 patients left in the world from this early era (Table 4), all ing been given kidneys from blood relatives.275 Other techniques followed. The most important new variable between 1962 and 1978 was adjuvant use of antilymphocyte globulin (ALGI added to prine (or to cyclophosphamide) and steroids.276 Ultimately, it came possible to produce more potent and specific ALGs277 with hybridoma techniques discovered by Kohler and Milstein.278 0 12 24 36 48 60 ever, from 1963 to 1979 with any of the methods available, truly MONTHS AFTER TRANSPLANTATION ceptable results were obtained only with renal transplantation consanguineous donors. Candidates for liver transplantation faced with the bleak prospect of receiving a nonrelated (cadave survival rates (life table method) for children (patients less than 18 years of age graft. they received their primary liver graft) and adults (patients 18 years of age or older The situation changed drastically for recipients of all kinds of they received their primary liver graft). Eighty-five patients less than 18 years of age daveric organs, including the liver (Fig 46), with the disclosure treated with azathioprine (AZA) and steroids, and 438 were treated with cyclosporine 'A) and steroids. Eighty-five patients 18 years of age or older were treated with azathi rine and steroids, and 1,031 were treated with cyclosporine and steroids. TABLE 4. Renal Transplant Recipients Treated Before and associates of the phenomenal immunosuppressive quali 31 March 1964, Surviving in September 1989* of cyclosporine,279 with the initial clinical trials of this agent for No. of Original ;;aaaveric renal transplantation by Caine and co-workers/ 80' 281 and Patients Graft the systematic combination of cyclosporine with steroids and University of Colorado 282283 14 10 immunosuppressive measures. ' Although cyclosporine Medical College of 3 3 Virginia steroids are the baseline drugs, azathioprine is often used as a University of maintenance agent to reduce the required dose of cyclospo- 2 2 Minnesota 289 or it has been used in some cases to replace cyclospo Necker Hospital (Paris) altogether after a few months or longer. Antilymphocyte globu- 1 0 Peter Bent Brigham 290 293 1 1 preparations,284 including the monoclonal antibody OKT3, - Hospital (Boston) been given prophylactically, later in the postoperative period Western General 1 0 the specific indication of rejection, because nephrotoxicity of cy Hospital (Edinburgh) Cleveland Clinic necessitated its use in low doses, or both. 1 1 Total 23 17 'Data presented at the Sixth Capri Conference of and Its Limitations Uremia. From Starzl TE, Schroter GPJ, Hartmann Cyclosporine has been the single most important factor in making NJ, et a!: Long term (25years) survival after re transplantation a practical way of treating hepatic disease (see nal homotransplantation- The world experience. Transplant Proc 1990, (in press). 46). However, the drug's principal side effect of nephrotoxi city280' 281' 294 puts a cap on its permissible dosage. Even with the 72 73 regeneration response>after effect that has been con _ - V -----~~~~VOGO294 (jf cyclosporine fll. chug l.:UL:KldJll) human recipients oflivers - 299 and hearts,300- 302 evidence of The mechanisms of this seeming he nal dysfunction has included azotemia, hyperkalemia, and i-\Nilfibe important to determine for another reason, tension. Because the morphologic changes in the kidneys nf for cyclosporine but for other drugs. It is now known that patients may not be reversible,297' 302- 304 the extent of the · liver promptly goes through a period of volume ad- liability of either short- or long-term cyclosporine therapy has yet shrinking or enlarging to conform to an appropriate size be determined. particular recipient.323' 324 It may be speculated from non When cyclosporine was first used clinically in 1978 through 1981 experiments325 that control of liver size is hormonal, with assays were not available to monitor blood or plasma levels. most dominant factor being endogenous insulin. Interference or function was used to guide dosage, the objective being to give of the hepatocellular growth control that is responsible have practical implications. closporine to the limit imposed by its nephrotoxicity.298· 305· 306 is much to be said for this approach even today. However, there is demonstration that cyclosporine enhances regeneration has tendency to guide cyclosporine doses by frequent measurements further experiments to elucidate its hepatotrophic prop . blood307 or plasma trough concentrations with The model has been the dog submitted to end-to-side porta (Fig 47).3 livers Eck fistula (RIA), high-performance liquid chromatography (HPLC),308 or shunt The in animals with undergo rescence polarization immunoassay (FPIAJ. 309 A trough whole atrophy and organelle disorganization within 4 days. The most cyclosporine concentration of 250 to 450 ng;mL (HPLCJ, 800 to organelle change caused by Eck fistula is disruption of the endoplasmic reticulum with depletion of its ribosomes.3' 325 nglmL (RIA), or 3091,000 to 1,600 ng;mL (FPIAJ is normally considered be therapeutic. However, these so-called normal the same time, the rate of hepatocyte mitoses per 1,000 hepato 3 vary greatly from center to center. In addition, therapeutic increases from 1.5 to 4.5. trations for cyclosporine are dependent on the other pressive310311 drugs used and may decrease with time after tion. ' Although some patients maintained at "therapeutic centrations" have exhibited cyclosporine toxicity, others above the "therapeutic concentration" may n·otmanifest any toxic symptoms all. The maintenance of stable cyclosporine concentrations in transplant312 patients is more difficult than in recipients of other gans. The changing quality of graft function postoperatively biliary duct obstruction or the presence or absence of T-tu 314 15 drainage, bile fistulas/ and numerous other factors common in Pump or specific to liver transplant patients 316 make cyclosporine monitor ing even more317 important than it is for kidney and heart transplant recipients, providing reliable in-center standards are established. CsA Cyclosporine and Liver Regeneration The ability of the liver to regenerate after being injured is an im portant consideration in any kind of major hepatic operation, but especially after liver transplantation where recovery from ischemic injury or from rejection is required in most cases. In addition, many 47. chemotherapeutic agents inhibit regeneration, including doxorubi use of an Eck fistula (portacaval shunt) model for the study of drugs such as cyclo 318 9 (CsA). The model, in effect, splits the liver into two fragments that differ only by cin (Adriamycin), ':-n which might be given to patients undergoing is infused into the tied-off left portal vein branch. Each experiment serves as its own liver replacement for hepatic malignancies under cyclosporine im , since the directly treated (left lobar) and control hepatocytes that are exposed to munosuppression. Consequently, it was important to know what ef- irculate a drug (right lobar) are present in the same liver. (Redrawn from Starzl TE, Par 74 KA, Watanabe K, et al: Lancet 1976; 1:821-825. 75 dogs are. hot affected by the insulin infusions, meaning the insulin largely is consumed or inactivated with the first hepatic passage.325 This same experiment has been performed with infusion of closporine instead of insulin into the left portal vein? 26 The sporine in appropriate doses prevents hepatocyte atrophy 48. pletely and increases proliferation slightly on the side of infusion. of activated lymphocytes from human biopsy specimens with interleukin (/L2). contrast to insulin, the cyclosporine effect is almost as pronounce Starzl TE: Transplant Proc 1988; 20[suppl 3):356-360. Used by permission.) in the contralateral (right) liver lobes as in the infused ones. The that the cyclosporine hepatotrophic effect is not removed on it possible in tissue culture experiments to dissect the mech passage through the liver is of considerable interest, of drug action as these affected lymphocyte populations, to since the liver is thought to be responsible for more than 90% of the intrinsic cytotoxicity of the agents on cell cultures, and to degradation of this drug. A predominantly first passage removed in highly quantifiable test systems the interactions (includ- its hepatotrophic effect might have implied that cyclosporine is synergism) of different drugs. It has been possible with a few liver-specific drug in other biologic actions as well, not excludiiJ of effort to acquire information that previously was completely immunosuppression. The Eck fistula model with selective ;ible or that required years to accumulate. 339 branch infusion may be a useful experimental device to study and associates,337 ' 338 Fung and colleagues, and Duques- effects of other orally administered drugs on the liver and to and co-workers340 in Pittsburgh have referred to these tech how the liver alters these agents as they are picked up from as minitransplant models. From biopsy specimens of hearts splanchnic venous bed during intestinal absorption and brought livers, they obtained cultures of primed lymphocytes that had the liver. exposed to donor-specific antigen by virtue of transplantation 48). When donor spleen, which is saved at the time of organ bar- A NEW DRUG: FK 506 Until recently, only four drugs had been demonstrated to liver graft survival in large animals: (1) azathioprine/ 27 (2) phocyte serum and its globulin derivative (ALG),276 (3) and (4) the cyclosporine analogue Nva2 -cyclosporine.""'tl Recently, efficacy of a new agent, FK 506, was demonstrated after canine 330 331 transplantation. ' This agent might permit refinements of clilH'-'<1. iinmunosuppression. FK 506 was discovered in Japan less than 5 330 332 335 ago and reported in the literature for the first time in 1987. ' - reasonably clear picture of the conditions that will permit the most fective and safest use of FK 506 has emerged from these studies. practicality of combining FK with other conventional agents shown with canine kidney and liver transplantation, 331 in which therapeutic doses of FK, cyclosporine, and steroids provided as results as have ever been reported in dogs with any drug regiinen. The concept of drug synergism for immunosuppression is an mnhr""·"te culture technique in which human lymphocytes obtained from biopsy speci 273 one but difficult to prove until recently. Now, the interaction cultured and exposed to donor cells. Clonal expansion results. (From Starzl TE: drugs can be studied with great precision by measuring their Proc 1988; 20[suppl 3]:356-360. Used by permission.) 336 337 on mixed lymphocyte culture systems. ' These techniques 77 76 ·aJ-A\- ANTIGEN ~ DONOR PRIMED CELLS CELL - ANTIGEN PRIMED CELL INHIBITION OF EXPANSION FIG 50. Prevention or inhibition of clonal expansion in primed human lymphocyte cultures by FK tion of cyclosporine (CyA) or other drugs. (From Starzl TE: Transplant Proc 1988; of "rogue" clones by the addition of the experimental drug 506 and 3]:356-360. Used by permission.) (CyA). (From Starzl TE: Transplant Proc 1988; 20(suppl 3]:356-360. Used by ) vest and preseroed, is added to the recipient lymphocyte FK 506 all are synergistic with each other with in vitro the "primed" recipient lymphocytes proliferate (cell expansion) 342,343 very little delay (Fig 49). The mechanisms of the expansion studied qualitatively and quantitatively by collecting IL-2 or synergism of FK 506 and cyclosporine has been demon lymphokines from the culture medium and adding them to equally clearly with heterotopic heart transplantation in pendent cells. The proliferation or other response The synergism of FK 506 and cyclosporine is of special since the two drugs have similar, if not identical, ac- these IL-2-dependent cells provide an end point for a biologic 334,336,337 The ability of cyclosporine or other drugs to prevent this 506 is remarkably nontoxic at therapeutic dose ranges in sion of a human lymphocyte population is illustrated in Figure 344 345 ' It can cause convulsive vomiting and lethal emaciation the liver or heart biopsy specimens of patients undergoing severe 330 346 348 . • - Widespread arteritis was described in the organs even intractable rejection, clones of cyclosporine-resistant 347 348 cytes have been found side by side with sensitive clones (Fig 51) ' but in subsequent studies, these lesions were found in control animals as well as in those given cyclosporine, ste In such cases, FK 506 used alone or added to cyclosporine 331 eliminate the rogue clones (Fig 52).342 Cyclosporine, or both. Although one group has described alarming side of FK 506 in baboons/ 49 further studies have been reassur- 350 In appropriate doses, the drug use alone in outbred ba- CyA recipients has allowed nearly uniform survival of kidney ho with minimal toxic side effects.350 J trials with FK 506 recently were started in Pittsburgh, and CyA "RESISTANT" first dose was administered to a human on 28 February 1989. ~atientis a 28-year-old woman who had been given three liver @-•< over a period of 3 years. In addition to losing the first two liv ANTIGEN PRIMED chronic rejection (Table 5), the recipient had developed renal CELL to which cyclosporine nephrotoxicity was thought to have I CyA "SENSIWE" After FK 506 was started, rejection of the third liver graft promptly controlled by histopathologic criteria (Table 6), with improvement of the liver chemistries (Table 7). How FIG 51. her renal failure was not improved, and on March 27, 1989, ca- Development of cyclosporine (CyA}-resistant clones in liver or heart biopsy renal transplantation was carried out with immediate and that were undergoing clinical rejection. (From Starzl TE: Transplant Proc 1988; 20[s 3):356-360. Used by permission.) good renal function (Table 8). In this and all subsequent treated chronically, cyclosporine was eventually discontinued. 78 79 Duct Loss Fibrosis .. 0 0 0 Cryptogenic cirrhosis 0 1+ 0 0 0 1 7/2/85 Chronic rejection 15 0 0 0 0 2 12/28/87 Chronic rejection 69 0 2/28/89 3 6/29/88 0 1+ 1+ 0 2 38 53 0 Sclerosing cholangitis 0 0 1+ 0 0 1 11/9/83 Primary nonfunction 12 0 0 0 0 2 11114/83 Chronic rejection 34 0 0 0 94 0 3 12/6/85 Hepatic artery 1+ 0 0 4 2116/86 Chronic rejection 0 2+ 0 0 0 3/25/89 5 1/1/89 Hepatic artery 14 0 0 0 0 (late) 31 0 6 7/2/89 1+ 0 0 3 30 55 0 Autoimmune 0 1+ 1 6126184 2+ 0 2+ 0 3+ 4/4/89* 2 ll/18/87 1+ 0 z+ 4 43 52 0 Polycystic liver and 14 1+ 0 1+ 1+ kidney 51 0 4/8/89 1 11/21/88 3+ 0 0 0 1+ 5 42 65 0 Cryptogenic cirrhosis 2+ 0 1+ 6/2/89 1 4130189 12 +I- 6 38 49 0 Cryptogenic 1+ 1+ 0 0 1+ 6/29/89 1 1212182 1+ 0 0 7 47 100 0 Sclerosing cholangitis 18 0 7/1/89 1 6/15/86 2+ 1+ 1+ 0 2 8 18 63 0 Cryptogenic cirrhosis 1+ 1+ 1+ 1 5/13/86 Chronic rejection 16 1 . b . · · nd 3+ being extensive injmy. 7/8/89 2 7/18/86 from 0-3+, wtth 0 emg no m)ury a . I t inin for hepatitis B core and surface diagnosis of cellular rejection was mco~ect;stahepftic failure, although FK 506 was 'Because the allocated supply of IV FK 506 had been depleted, FK 506 was stopped on 8/5/89 :ec_m was positive. Patwnt no. 4 progresse to mman and cyclosporine was resumed. When FK 506 and cyclosporine were used together, blood levels tended to rise with consequent aggravation of of Liver Function Tests to FK 506* ~----- GGTP SGPT Alkaline Phosphate rine nephrotoxicity. The cadaveric kidney graft of patient SGOT (lUlU (lUlL) (JU/L) which has never been exposed to any baseline drug except for Day \mgtdLI (JU/L) 71 506, has had no evidence of nephrotoxicity. 49 47 160 0 0.6 45 The same improvement in liver function has been noted in 24 24 145 7 0.6 42 31 36 131 patient except one (patient no. 4), whose initial diagnosis of 14 0.5 24 11 10 75 4.5 months after combined liver and kidney transplantation 28 0.2 37 17 17 111 to be incorrect. Within a few days, it was realized that this 56 02 22 20 19 94 143 0.2 17 had fulminant hepatic failure due to B virus hepatitis, and the 29 27 90 506 was stopped. Despite retransplantation, the patient died. 156 0.3 167 142 345 The remarkable effectiveness of FK 506 in patients for whom 0 1.3 109 2 277 172 previous therapy had failed, as well as the seeming lack of toxicitY 0.7 46 109 7 (Continued.! these patients, has been noteworthy. From the preliminary 81 80 BUN* Creatinine 0.5 29 30 (mg!dLJ (mg!dLJ 0.4 29 36 70 50 2.5 lOSt 3.6 33 105 514 7 150 737 18 0.4 98 4.1 116t 1.9 80 171 858 14 0 281 18 0.7 81 4.1 123t 1.2 35 29 311 28 0 0 18 0.3 51 2.8 130t 0.7 28 31 352 56 0 0 18 0.5 38 1.4 143t 0.9 46 71 394 143 0 0 18 0.4 29 1.4 3 0 0.6 156 0 0 18 0.4 23 1.3 32 32 121 7 0.5 41 31 117 1,600 14 0.4 0 255 0 0 37 1~ 26 24 96 28 0.2 7 100 810 18 0.4 50 zn 11 10 99 14 0 0 18 0.7 61 2~ 56 0.6 26 9 81 28 0 0 18 0.2 45 ZA 102'1: 1.7 53 20 192 56 0 0 9 0.3 38 ZA 124* 1.9 56 49 297 109 0 0 6 t 1.1 111 3B 4 130 0 0 3 t 0.4 63 1~ 0 2.3 287 312 144 143 0 0 9 t 0.9 65 ZB 5 0 20.5 63 79 417 3 0 150 214 0 0 84 5A 7 13.6 60 72 386 7 0 0 18 1.0 95 6.5 14 9.3 47 60 257 14 0 0 18 1.0 88 5.8 28 3.8 38 61 305 28 56 1.9 0 0 12 0.7 60 5.8 31 38 229 63 1.5 124* 50 < 50 0 0.1 34 3.2 9 39 194 69 1.5 13 38 173 4 0 800 1,621 0 0 75 2.4 6 0 2.5 339 634 348 5 0 2,000 967 0 0 25 0.6 7 0.7 33 107 283 7 150 1,373 20 4.0 49 1.4 14 0.5 46 95 557 14 150 148 18 1.2 49 1.7 28 0.5 93 114 409 28 150 190 20 1.9 46 1.4 46 0.5 52 75 246 56 150 324 20 0.6 40 1.5 7 0 2.1 69 0 0 20 1.2 40 1.6 198 550 304 7 1.6 40 236 250 6 0 100 154 0 0 55 2.3 14 1.2 135 600 523 7 100 160 16 1.2 65 2.7 28 0.7 94 324 501 14 0 76 16 0.9 82 3.8 41 1.8 114 408 555 28 0 0 16 NA. 55 4.0 8 0 3.7 46 0 0 16 2.1 58 3.5 713 609 268 7 1.2 318 284 176 14 1.1 7 0 250 482 0 0 38 2.1 175 128 119 28 0.8 7 100 615 30 NA. 37 2.5 84 90 106 38 14 100 292 30 3.9 41 2.4 0.5 74 86 142, 28 0 0 30 1.8 57 2.9 •TBIL = total bilirubin; SGOT = serum glutamic oxaloacetic transaminase; GGTP = gamma trans peptidase. 41 0 0 30 2.1 49 3.1 tNew liver allograft Isee text I. *On N hyperalimentation (see text); FK 506 stopped on day 124. 8 0 440 845 0 0 29 1.1 7 100 444 18 3.1 40 2.6 (Continued.) 8.2 83 DIAGNOSIS OF 0 18 38 0 0 9.5 3.9 29 GRAFT DYSFUNCTION 'BUN = blood urea nitrogen. tFollowing liver transplant (see text). *Value on hemodialysis. tions made with FK 506 as a salvage drug, its efficacy and a liver graft fails intraoperatively, nonimmunologic factors seem beyond question even at this early stage. A trial of FK the primary suspects, even though there may be exceptions, as the primary drug in liver transplantation was started in August 1 ed in the previous section. The frame of reference quickly A very important observation in the patients with FK 506 has thereafter. Immunologic rejection as an explanation for almost immediate relief from the severe hypertension from graft dysfunction becomes increasingly probable with each each of the patients except patient no. 4 were suffering. The day after transplantation, particularly if the new liver pertensive therapy was greatly reduced or stopped altogether to be satisfactory at the outset. Nevertheless, nonimmuno these patients. explanations for delayed graft failure or dysfunction must be At the annual meeting of the European Society of Organ ruled out. During the first several postoperative plantation, which was convened on October 31, 1989, a complete , the diagnostic possibilities include suboptimal revascular port of FK 506 was given, including exposition of the Pittsburgh as already discussed; defects in bile duct reconstruction ical trials. The FK 506 has been synthesized, and its binding site obstruction or fistula; opportunistic viral infection with cy 354 354 been identified by Dr. Stuart Schreiber of Harvard University. (CMV),353' herpes simplex virus (HSV) or viruses, 355 356 357 binding site, which has been called Fujiphilin, is different than virus (EBV), or adenovirus (ADV) ' ; infection by a cyclophilin binding site for cyclosporine. of bacterial or fungal pathogens 358; toxicity from hyperali- 144 145 In the meanwhile, an additional drug with a very similar rh<>rnir or sepsis ' ; and hepatotoxicity of the drugs used to structure has been isolated by workers of the Ayerst rejection359' 360 or for other purposes. 361 Graft dysfunction Corporation from the fungus Streptomyces hygroscopicus351 at a somewhat later time can be caused by recurrence of called rapamycin. This drug has been described as having pow<>r disease that destroyed the native liver, infection of the transplant immunosuppressive qualities in rodents and dogs.352· It seems one of the hepatitic viruses, defects of bile duct reconstruction, or that the FK 506 is the forerunner of a new and extremely inter"'" ic rejection. Each general cause of graft dysfunction except class of drugs that may have a potency and safety profile already covered will be expanded on in the following sections. enough to make them competitive with or possibly superior to closporine. AND TOLERANCE INDUCTION Like other immune responses, rejection can be separated into distinct but overlapping phases: (1) recognition of the antigen , (2) development of response capable of neutralizing the (effector), and (3) regulatory mechanisms that restore ho- stasis. to the organism.362' 363 It is likely that there are several dif inductor, effector, and regulatory pathways involved in each .362' 363 Clinically, effector mechanism receive the most atten since recognition and attempts to control this process are the 84 85 Aside .from its resistance to humoral rejectioli (see earlier 80 381 the liver displays some special properties as a solid organ recipient liver? ' Auxiliazy grafts animals therefore serves as wapamy rejected, and the recipient becomes sensitized both and humans and an 380381 good model to study each phase of the rejection response. result. ' The reasons for these observations are largely un . however, the immunogenecity of the liver seems to reside after the367 initiation of human liver transplantation, Cordier and ciates as well as others 368 discovered that liver allografts in in the nonparenchymal cell fraction. Sensitization rather do not follow the normal laws of transplantation. They found tolerance develops following infusion of unfractionated liver suspensions that contain both parenchymal and nonparenchy- porcine hepatic grafts experienced prolonged survival with little 382383 no immunosuppression. Caine and co-workers369- 371 elements?80 Lautenschlager and others ' infused crude that along with the immunologic "privileged" status, porcine liver of liver-derived cells in an attempt to prime recipients rejection of subsequent heart grafts. They found little immuno lografts also induced a state of hyporesponsiveness to other 382383 from the same donor. In contrast, no spontaneous long-term liver city associated with the fraction enriched in hepatocytes, ' lograft survival was seen in the dog, baboon, rhesus monkey, or the Kupffer cell fraction, which may also have contained mans, all of whom required immunosuppressive therapy to cells, was potently immunogenic. 372 tain graft viability. Later, Zimmerman and colleagues373 and 273374 376 mada and others ' - demonstrated that inbred strains of Mechanisms Underlying the Unique Properties of Liver experienced a phenomenon similar to that seen in pigs. Since 'lograjts in Rats the rat has served as an invaluable animal model for the study 213 376 Genetic control of the allogeneic immune response is the most ob liver transplantation. ' The resistance of the liver allograft to reason for the nonresponder status in rats, since the phenom peracute rejection has already been discussed. described earlier occurs only between certain strain combina As might be expected, in rat liver transplantation the alloge Tolerance Induction and Immunosuppression Induced by Rat Transplantation response appears to be under the control of primarily the im response gene (Ia or class II MHC), but minor polymorphic 2 376379384 As mentioned previously, liver allografts are permanently C loci may also influence the reaction. 1.3, ' ' Although no without immunosuppression between certain strains of rats (e.g., concept has been described to explain the peculiarities as to PVG), whereas in others, the liver is acutely rejected.213· 376· 377 •u~,.;•a.t~uwith rat liver transplantation, many of the effects observed class II MHC antigens appear to be the most influential in rl<>tPT'Tn similar to those seen when attempts are made to regulate other ing the rejector status of the strain combinations. 213· 378· 379 responses. Kamada and Wight,374 Zimmerman and col even across full RTl haplotype mismatches, liver allografts are and Roussin and associates214 reported that rat liver al ated in these nonrejector combinations, whereas other organs ( secrete soluble MHC antigens in the circulation where they skin, heart, and kidney) are acutely rejected.374- 376 The liver to antigraft antibodies, rendering them nontoxic. However, it also induce a state of donor-specific unresponsiveness in been difficult to detect circulating immune complexes. Human recipient that permits subsequent transplantation of the skin, 11 213 375376 allografts also secrete these MHC products/ and their binding or kidney grafts. ' ' Liver grafts performed on the same day preformed antibodies is one mechanism whereby the livet is the kidney or heart graft can prevent subsequent rejection of 374 to be relatively resistant to the effects of preformed lympho of these extrahepatic organs. However, a period of at least 5 c:.vtotoxic antibodies. 385 is required 374between the liver and skin grafts to achieve Kamada and associates have also shown that serum from liver acceptance. Liver grafts are even able to reverse cellular rejectioJ -tolerant (LGT) rats can cause donor-specific enhancement of in cardiac grafts transplanted 5 to 6 days before the liver.213· 376 grafts, and the enhancing activity has been localized to the potent tolerance-enhancing effect is also capable of reversing a antibody subfraction.386 Lymph fluid from LGT rats exhibits a sensitized state (i.e., removing circulating allogeneic antibodies 213 376 213 376 effect but requires daily administration. ' memozy cells). ' However, when liver grafts are transplanted Although liver grafts are eventually tolerated between nonrejec- 86 87 .ullutu 5 • .._, reaction elicited by a genetic disparity subside, and the class I antibodies return to baseline.388 Pe--,~L the doribr and recipient, which demonstrates both sped high-titer anti-class II antibodies subsequently appear and memory. The response is largely T-cell dependent and is partially responsible for maintenance of the graft.213· 376· 387· 388 by the cell surface glycoproteins encoded by the MHC munophenotypic analysis of graft infiltrating cells during the on chromosome 6 in humans. Not only are these antigens sient rejection episode in nonrejector rats reveals a profile of targets on the transplanted tissue, but they assist in quantitatively similar to that in rejector strain combinations. 389· of the recipient rejection response. 398 Other antigens Qualitatively, however, the ratio of T cells to non-T cells and in the rejection response include the major ABO helper cells to T-suppressor/cytoxic cells are increased over time group system, minor MHC antigens, and possibly tissue nonrejector combinations compared with the rejector strains.389' antigens.362' 363 In addition, eventual hepatocyte necrosis with architectural the observation that MHC antigens provoke strong rejec- lapse, which presumably is the result of the vascular responses when they are part of an allograft, as isolated anti never develops in grafts that are eventually tolerated they are, in general, considered to be relatively weak immuno observations). 362 363399 within species. ' ' A strong in vivo cytotoxic T~lympho Adoptive transfer of thoracic duct lymphocytes of LGT rats has response to these antigens requires not only the antigen but effect in the immunologically crippled host.213' 376 However, a second signal, or costimulus, which is provided by a viable of graft-infiltrating lymphocytes restores the alloreaction, cell.399 that clonal deletion of donor-specific effector cells occurs within accessory, especially "dendritic" leukocytes 375376 or passenger liver graft. ' Despite the inability of the animal to reject the capable of presenting both the foreign MHC antigen and provid in vitro, lymphocytes from LGT rats proliferate in response to the second signal, or costimulus. 399' 400 The ability to respond de lymphoid cell and generate CTLs.213' 376 Also, in vivo localized to alloantigens has been attributed to the diversity and cross vs.-host (GVH) lymph node reactions remain intact. This within the antigen and MHC restriction element sites on 213 376 401 404 non has been termed split tolerance. ' Splenic suppressor T-cell receptor complex. - Clones that normally recognize 391 have also been identified. Similar immunologic findings have X (e.g., viruses) complexes can cross-react with alloanti reported in nonrejector pig strain combinations 392 and in some -404 Alternatively, the donor MHC antigens may be pro 393 man liver allograft recipients. by recipient antigen-presenting cells, similar to other types of The immunologic observations in LGT rats are similar to antigens.362' 363 seen in antibody enhancement studies. The antigen reactive structures within the allografts that trigger the alloreaction opsinization (ARCO) hypothesis has been used to explain the not been identified with certainty, nor is it known whether the tionship between delayed-type hypersensitivity responses, ctive phase occurs within the graft, systemically, or both. Liver are thought to be important in rejection, and antibody offer a unique opportunity to study the sites of sensitization This hypothesis incorporates a role for antigens and antibodies, of the strict structural anatomy of the organ. In a "norrrial" pressor cells, splenic sequestration, and clonal deletion of planted liver, such as a donor liver prior to transplantation, tive cells in the liver, all of which are reportedly seen in LGT is strong expression of the major ABO blood group antigens on The position of the liver in the circulation and the function of venous and capillary endothelium and bile duct cells.405 He intrahepatic reticuloendothelial system may be important in this do not express any of these antigens. The class I MHC an gard. Several groups have reported prolonged survival of various are expressed strongly on the bile ducts and somewhat more lografts following portal venous inoculation of allogeneic cells.395' on the sinusoidal cells and endothelial cells. Class I MHC an However, others have been unable to reproduce this are barely detectable on hepatocytes. Class II MHC antigens and Starzl and colleagues have questioned the experimental DQ, and DP) are expressed only on capillary endothelium, 3 and rationale of this approach. cells and dendritic-shaped cells within the portal tri- 88 89 . --.u.Y nuue attention has been given to the possible deO Several pathways have been implicated in the effector phase of alloreaction: direct antlbo Effector Pathways Several pathways have been implicated in the effector phase of dama ~::, alloreaction: direct antibody and complement mediated 0 delayed-type hypersensitivity responses, cytotoxic T lympholysis, and antibody-dependent cell cytotoxicity mediated through killer 362363416 422 cells. ' · - All of these effector pathways are dependent on T FIG 53. lymphocytes.362, 363,416-422 Early histologic events in rejecting rat liver allograft (BN->DA). A, the early evidence of the alloresponse occurs at 2 days and consists of mononuclear cell sludging in the capil These pathways roughly correspond to clinical classification of re laries (inset) and interstitium of the portal tracts. B, closer examination of this population 363 jection.362' Direct antibody and complement-mediated damage is reveals mitotic figures (arrows), suggesting that some sensitization may occur within the largely responsible for triggering the cascade of events resulting in graft. C, by 4 days, the infiltrate begins to tunnel beneath the portal vein endothelium (ar hyperacute rejection. Delayed-type hypersensitivity and allogeneic row); D, by 5 days, venous damage and infiltration jnto the ducts are noted (arrows). E, cytotoxic T lympholysis play principal roles in acute cellular rejec preterminal changes at 12 to 14 days include portal-portal linkage, centrilobular collapse, congestion and hemorrhage (pt =portal tract; cv =central vein). (From Demetris AJ, Qian tion, and chronic rejection most likely represents a vascular directed attack by a combination of both cellular and humoral immunity. S, Sun H, et al: Am J Surg Pathol [in press). Used by permission) However, the present clinicopathologic classification of rejection CLINICOPATHOLOGIC FEATURES OF REJECTION into hyperacute, acute, and chronic rejection is not ideal, particu larly with regard to the liver, and is probably in need of revision. Acute Cellular Rejection Nevertheless, we will adhere to conventional terminology in the The physiologic and morphologic features of cellular rejec- present review. tion were worked out long ago in experimental ani mals.8' 9· 18· 74· 81· 186· 327· 423 Improvement in patient survival (and wide- 91 90 common and principal manifestation of the rejection reaction. episodes occur between 6 or 7 days and 6 weeks after but may be seen as early as 2 or 3 days after the operation. Episod occurring later than 2 months usually, but not invariably, associated with decreased levels of immunosuppressive The clinical signs of acute rejection include fever, lethargy, tenderness, leukocytosis, and a change in the color or quantity 18 66 67 74 435 437 438 bile. ' • ' ' - Peripheral blood and graft eosinophilia ' and lymphocytosis440 have also been associated with rejection, have increased levels of serum neopterin, 441 soluble IL-2 receptors, 443 444 -microglobulin, guanase, amyloid A protein, and ~2 but none these alterations appears to be entirely specific. Serum bilirubin is sensitive marker of dysfunction, and hepatic enzymes indicative liver injury are frequently increased, but neither the absolute 18 66 7 74 435 nor the pattern of elevation is specific for rejection. • • <' • • - Confirmation of a clinical suspicion rejection is usually achieved core needle biopsy evaluation.* The histologic diagnosis of acute cellular rejection rests mostly identification of a predominantly mononuclear portal tract inflaul" matory infiltrate, along with evidence of tissue damage (Fig 54) .-t should be emphasized that portal inflammation alone may be due many causes and therefore is not diagnostic of rejection. The accumulation of mononuclear cells occurs in the interstitium of portal tracts. Tissue damage becomes manifest as the infiltrate tends into the walls of the portal vein and bile ducts, associated with reactive changes in the target cell populations (endothelium and bile ducts) such as hypertrophy and nuclear enlargement. Evidence pyknosis and focal necrosis is also seen. Cytologically the rejection infiltrate consists of an admixture large blastic lymphocytes, smaller lymphocytes, plasma cells, macro FIGHistopathology 54. of acute cellular rejection in humans. Events are almost identical to those phages, eosinophils, and neutrophils. Eosinophils may predominate seen in the rat (see Fig 53). A, mild acute cellular rejection. B, in moderate acute cellular in some cases during the early phases, simulating an allergic drug rejection, the infiltrate is somewhat more !\arid, but no signs of ischemic parenchymal or 144 145 428 438 reaction. ' ' ' Immunophenotypic analysis of the rejection interstitial injury are detected. C, subendothelial infiltration of lymphocytes in the portal veins and, 0, infiltration and damage of small bile ducts (arrow) are characteristic and di infiltrate demonstrates a preponderance of T cells with both CD4 + agnostic features. E, severe acute cellular rejection is diagnosed when there is evidence or CD8+ subsets; non- T cells, such as macrophages, monocytes, as 238 409 411 445 446 of acute rejection-related ischemia, such interstitial ilemorrhage, necrosis, and cell neutrophils, and B cells, are also present: • • • • dropout (pt = portal tract; cv = central vein), or F, inflammatory or necrotizing arteritis. Hepatic arteries within the portal tract are difficult to locate dur (From Demetris AJ, Qian S, Sun H, et al: Am J Surg Pathol [in press]. Used by permis- ing an acute cellular rejection episode. Endothelial swelling and mu ral hypertrophy are the most common observation when the arteries sion.) are found. Necrotizing or neutrophilic arteritis (or both) is rarely *References 67, 118, 119, 144, 145, 179, 423-436. -rReferences 67, 118, 119, 144, 145, 179, 423-434. 93 9Z --.1-----~~ --~ ------_J affected are the second~ in use in Pittsburgh adapts con of the hepatic artery in the hilum, which are not accessible to , , rieart grafts (Table 9)?44' 145 As in the ex 144145424427428 biopsy evaluation. • ' ' ' The rather low incidence of orgcmsFtfte':S~parationfrom mild to moderate acute cellu tis detected in needle biopsy samples may therefore be due ction is somewhat arbitrary and is based on the exuberance sampling problem.144, 145,424, 427,428 inflammation, which may have little prognostic significance. Surprisingly little inflammatory cell infiltration into the rejection, on the other hand, is diagnosed when there is his lobule is seen during rejection. In fact, if significant lymphocytic evidence of rejection-related vascular compromise (ischemic patocellular injury is detected in biopsy samples, a de novo or , interstitial hemorrhage, and/or arteritis. The problem with rent viral hepatitis is more likely to be the cause of graft ulying such a system in the liver is that arteritis is rarely observed The relative restriction of the inflammation to the portal tracts biopsy samples, and apparent ischemic parenchymal changes rejection may be the result of the functional anatomy of the organ, be nonspecific or unrelated to rejection. It may be that a se localization and concentration of MHC antigens, and possibly the lo~ analysis of serial biopsies demonstrating continual deterio 43 452 cation of portal dendritic or capillary endothelial cells.409· 414 is more predictive. '' Fine needle aspiration biopsy (FNAB) sampling of the liver has Functional analysis of lymphocyte cultures derived from rejecting been advocCl.ted as an adjuvant to the needle core for routine immu liver tissues demonstrates both proliferative and cytotoxic 448449 339453 nologic monitoring. ' Although this technique appears to be reactivity directed at donor MHC antigens. ' The concept of in useful, it is diagnostically limited because no information is obtained vitro expansion of graft-infiltrating lymphocytes, which was dis on the architectural integrity of the organ, a problem that is of lesser cussed earlier (see Figs 50-54) in connection with drug develop significance in kidney grafts where FNAB is more routinely used. In ment, is based on the fact that the T cells activated in vivo express the liver, there are many more causes of graft dysfunction, complica~growth-promoting IL-2 receptors, and in vitro, the addition of IL-2 tions, and morphologic manifestation of systemic derangements, to the culture medium selectively expands the activated cells. Both which require attention to architectural detail. the proliferative and cytotoxic activities observed in lymphocyte The distributions of the MHC antigen in human livers is altered cultures can be blocked by specific monoclonal antibody directed at 339453 after transplantation451 presumably because of local secretion of lym class II or class I antigens. ' Functional analysis of the lympho- phokines.450' , Steinhoff and associates411 and Gouw and col leagues238 detected a weak expression of class I antigens on hepato cytes early after transplantation in the absence of graft pathology. So TABLE 9. Histopathologic Grading System of Acute Cellular Rejection and co-workers attributed412 this early presence to hepatocyte necrosis from harvesting injury. Weak class II antigen expression was de Grade Histologic Findings tected locally on bile ducts in the absence of cellular rejection. Dur 1. Consistent with Mononuclear portal interstitial infiltrate with "blastic ing rejection, class I antigens are upregulated on hepatocytes and lymphocytes but little evidence of tissue damage* bile ducts, and DR, DP, and at times DQ can be detected on biliary 2. Mild Mild predominantly mononuclear portal tract infiltrate with epithelia and endothelial cells.238' 409- 413 Steinhoff and associates evidence of bile duct damage with or without subendothelial were also able to detect weak DR expression on hepatocytes during inflammation 411 rejection and viral infection. Although several investigators have 3. Moderate Portal expansion secondmy to predominantly mononuclear inflammation with duct damage and spillover into the lobule detected an association of an altered display of MHC antigen with with or without periportal hepatocyte necrosis; no evidence of certain graft syndromes, the patterns per se were not generally spe arteritis, central or bridging necrosis (rejection-related cific for any particular cause of dysfunction. Alterations have been ischemia) detected during large duct obstruction and hepatic or systemic (or 4. Severe Usually marked but variable portal inflammation with evidence of both) viral and bacterial infections, in addition to rejection. · - interstitial hemorrhage and/or ischemic hepatocyte necrosis or 238409 413 Pathologic grading of acute cellular rejection is a controversial inflammatmy arteiitis, in addition to findings in no. 2 or 3 area. Several classifications systems have been proposed, but none is 'Diagnosis used most often in the first 3 posttransplant weeks when there is clinical and biochemical evidence of graft dysfunction but histologic findings are not diagnostic Isee text I. able to predict the likely response to therapy or eventual outcome 94 95 In general, lymphocyte outgrowth from the biopsy specimen relates well with the histologic diagnosis of moderate or severe 339 453 454 cellular rejection. ' ' However, alloactivated cells can be ated from biopsy specimens where the etiology of graft is due to viral hepatitis.453 The significance of this latter obseiVatinn has yet to be determined. Similar studies have been performed in liver allografts.4 s5 Chronic Rejection Recipients who develop chronic rejection usually experience a rel atively asymptomatic rise in the canalicular enzymes (alkaline phos phatase and ')'-glutamyl transpeptidase) and eventually become jaundiced.* Although the term chronic implies a temporally pro longed course, this syndrome can evolve within weeks after trans plantation or be the end result of acute rejection unresponsiveness to conventional therapy. Unfortunately, some of the patients will recapitulate the same course after retransplantation of a new 144 145 456 457 graft. • • • Synthetic function usually remains intact until late in the course, although rapid deterioration can occur in patients who. develop superimposed vascular thrombosis or biliary tract stricturing and subsequent cholangitis.145 Clinical suspicions of chronic rejection can be confirmed or ruled out after needle biopsy evaluation.t44, t4s, 424, 4s6, 4s7 Occlusive arteriopathy and bile duct loss (vanishing bile duct syn drome) are the principal structural consequences of this form of im munologic graft injury.t Although these cardinal manifestations may occasionally appear to occur in isolation, we have shown a close re lationship between the degree of arterial luminal narrowing and the 458 severity of bile duct loss. This dependency is not surprising con FIGHistopathologic 55. features of "chronic" liver allograft rejection. A, in the earliest phases ol sidering the arterial system is the only source of blood for the bile chronic rejection, the portal infiltrate is often unimpressive, but the duct damage is severe 146 ducts. This led us to suggest that two mechanisms are responsi (arrows) . B, eventually the bile ducts are totally destroyed; a finding recognized by the ble for the bile duct loss seen with chronic rejection: direct immu presence of .a portal artery without an accompanying bile duct. C, finally, the artery may nologic damage and ischemia.458 The Cambridge group has also be destroyed as well, and the portal triad becomes devoid of inflammatory cells. D, lobular shown that disparity at the class I MHC locus (see the discussion of changes include central hepatocanalicu\ar cholestasis, perivenular fibrosis, cell dropout, and mononuclear infiltration with occasional clusters ol sinusoidal foam cells (cv = central the effect of Histocompatibility) and CMV infection were interdepen 459 460 vein). E, large septal arteries (HA = hepatic artery) become occluded, usually by subinti dent predisposing factors for chronic rejection. ' In addition, mal loam cells, which causes ischemic injury and epithelial sloughing to accompanying patients with a positive pretransplant or posttransplant lymphocyto septal ducts (80 = bile duct). F, tibrointimal hyperplasia similar to the arteriopathy in kid 459 461 toxic crossmatch more commonly developed bile duct loss. ' ney and heart grafts can also be seen. (From oemetris AJ, Oian S, Sun H. eta\: Am J Surg The histopathologic features of chronic rejection are somewhat Pathol (in press]. Used by permission.) *References 67, 144, 145, 423, 424, 433, 434, 456, 457. tReferences 144, 14S, 423, 424, 433, 434, 4S6, 4S7. 97 96 postoperative liver recipient who has a skin rash should subtle and easily overlooked if one is not attuned to GVH disease to be expected. A skin biopsy specimen should features (Fig 55). In contrast to acute cellular rejection, the JLained. Although contim .._ l viability of donor lymphoid cells filtrate is often quite sparse and is comprised of been documented in the cases cited previously, replacement of plasma cells, and macrophages. Acute inflammatory cells are donor lymphocytes in grafted hepatic hilar lymph nodes has common. Despite the relative paucity of portal inflammation, 469 lial cell pyknosis, disruption of the basement membrane, and been shown. plete destruction of small bile ducts ensue.t This response that the effector mechanisms are extremely potent, ischemic in nature. Lobular alterations include Kuppfer's cell hypertrophy, spotty acidophilis necrosis like that seen in a low-grade lobular atitis, and eventual central hepatocanalicular cholestasis. Small ters of intralobular foam cells and perivenular hepatocellular phy, ballooning or dropout, and hemorrhage with sclerosis, ably a result of chronic ischemia, are end-stage features. bridging fibrosis is occasionally seen, a cirrhosis with rP.ctPnPr<> nodularity is uncommon. The obliterative arteriopathy that develops does so most monly in the branches of the hepatic artery in the hilum, 145 423 424 452 458 routinely sampled in needle biopsies . ' ' ' - Most arteries are narrowed because of deposition of subendothelial cells in the intima, the majority of which appear to be derived recipient macrophages. However, the presence of T and interdigitating reticulum cells can also be seen in the media and periadventitia,462 suggesting that cellular immunity volved in the development of these lesions. Concepts from sponse to injury hypothesis used to describe the atheroclerosis in the general population 463 appear particularly vant to the obliterative arteriopathy that occurs in the population. Graft-vs.-Host Disease Control of the rejection may not be the only requirement for ient survival. There has been increasing awareness that grafts can mount a significant attack on their recipient. The likely explanation is the persistence of donor lymphoid tissue in 423 464 465 liver grafts. ' ' The presence and continued viability of donor lymphoid implies the possibility of GVH disease, a that has been documented by the demonstration of new 2 7 464 465 donor-specific Gm types in the recipient~' ' and by the lysis caused by antihost RBC isoagglutinins, which are the lymphoid tissues in ABO-compatible but not identical livers 466 467 0 donor to A recipient). ' In addition, GVH disease has reported in a recipient whose own tissue .con!a,~!leddonor 468 cytes. Intensification of immunosuppress;io~·reli~~eda skin fever, and other symptoms of INFECTIOUS PROBLEMS IN LIVER TRANSPLANTATION AND FUNGAL INFECTIONS Although liver grafts may possess some immunologic advantage, discussed earlier, the practical reality is that heavy initial immu and later maintenance therapy are required in the way as with other organs. The balance between immunosup- sion and infectious disease control is more delicate than with and renal transplantation because the hepatic graft is ex to the intestinal tract through the biliary tract or by hematog contamination from the splanchnic venous bed. The devastat- role of consequent graft infection by organisms indigenous to (GI) tract was delineated in the early clinical tri- 358 436 473 475 470-472 as well as those in the cyclosporine era. ' ' - Ex in dogs performed 25 years ago provided an example of now is called bacterial translocation in that the liver graft itself a porous entry site for bacteria indigenous to the GI tract.476 liver damaged by rejection becomes unusually vulnerable to inva by such microorganisms. Effective immunosuppression has been recognized to be the only way to maintain intact tissue 8 and to avoid this kind of infection? / has been recent interest in controlling the bacterial and population of the GI tract with preoperative nonabsorbable 252 477 antibiotics. ' These antibiotics selectively suppress patho gram-negative organisms and fungi but allow survival of anaer This has been called selective intestinal decontamination. A antibiotic regimen consists of polymyxin E, gentamycin, and The morbidity from infection after liver transplantation has reduced with this approach, but the mortality has not.252 In to its unproved value, a practical limitation of selective de ~ntaminationis the inability to find a cadaveric liver at the optimal dained by the antibiotic preparation. about the subtle relationsljlips between host defenses and b.acteria remains to be learl)ied in the liver transplant model. host· macrophage system,. of. ;which the liver is an important 1 mponei1t,~~is profoundly altereP:by transplantation. The possi Kuppfer's cells in contributing to endotox earJil'lr s~sti!J~, mnression is lightened and especially if therapy is given with Liver also suffer from virus infections. recipients frequently (Gancyclovir) .479 ' 482 However, CMV strains resistant to currence of hepatitis viruses in grafts will be discussed in the 483 ~~i<>lmnrhave been reported recently. The onset of CMV is often section. Other virus infections occur at some postoperative 478 related to episodes of rejection, where the patient has the majority of liver recipients. received additional immunosuppressive therapy for an acute 353 354 478 480 rejection episode. ' ' - ~:~ically,patients usually present with a low-grade fever and CLINICOPATHOLOGIC FEATURES OF ALLOGRAFT VIRAL HEPA 1 elevated liver injury test results. Leukocytopenia,353 diarrhea,354 478 480GI Clinical symptoms, along with the use of core biopsy, are and respiratory symptoms are not uncommon. ' ' - establish the diagnosis of allograft hepatitis. In general, the diagnosis of liver involvement is confirmed by needle biop- features and histologic appearance of allograft viral hepatitidies 145,353 identical to those observed in other immunosuppressed patient hepatitis is characterized by lobular alterations is helpful, however, to anticipate the relative time of onset of 56).*144 • 145 • 353 Any cell type of the liver may be infected, and ferent viral syndromes, since they tend to occur at that are may demonstrate cytomegalic change, intranuclear times after liver replacement (Table 10) .* The following sections inclusions surrounded by a halo, and/or small baso separated into discussions of those viruses that are classically cytoplasmic inclusions. These foci are often infiltrated with ciated with hepatitis from those that are more opportunistic in of inflammatory cells, consisting of neutrophils, macropha ture. (microabscesses and microgranulomata), or both. Other lobular include mild Kupffer's cell hypertrophy. Significant lobu Opportunistic Viruses disarray, massive or submassive necrosis, or even severe liver The most common viral pathogens in the opportunistic from CMV alone is rare. Recognition of any of these changes that cause allograft hepatitis belong to the herpes family: CMV prompt a careful search for viral inclusions, the use of immu- types 1 and 2, varicella-zoster (VZ) virus, and EBV. Another allograft hepatitis not commonly seen in the general adenovirus (ADV). The following are presented in order of Cytomegaloviral Hepatitis The most common serious infections are with CMV, 353 354 478 48 can cause lesions in many organs. ' ' - ° Cytomeg is the most common cause of postoperative graft hepatitis is seen most frequently between 3 and 8 weeks after 353 354 478 480 plant. • ' - Protection from serious CMV infection has reported with hyperimmune globulin.481 Recovery is the rule if· TABLE 10. FIG 56. Characteristic histologic features of CMV Peak Incidence of Graft Syndromes vs. the Time After Transplant hepatitis include Kupffer's cell hypertrophy, spotty lobular necrosis (A, arrows) accompanied by microgranulomas or Cytomegalovirus 3-8 wk, often after treatment of rejection microabscesses (B); inclusions can be Herpes simplex Any time after transplant found in nearby cells (B, arrow). Epstein-Barr Most common in first 2 mo. but may occur anytime C,ytomegalovirus inclusions (C) can be Adenovirus 3-4 wk after transplant. found in any cell within the liver, including Hepatitis B Onset usually after 4-6 wk, and graft remains infected t)le biliary epithelium (arrow), where it has Hepatitis A No experience to date been.associated with loss of bile ducts non-A, non-B hepatitis ·Usually after 4 wk (see ~~xt). nohistochemical stains for the detection of the CMV both. Tissues containing rapidly dividing cells, such as young tion tissue, proliferating cholangioles, edges of infarcts, and 44 145 scesses or other defects are fertile soil for CMV growth? ' such tissue is encountered, a more careful search of CMV is 144 145 ranted. ' Finally, CMV can be associated with a plasmacytoid or uid:o;LH; filtrate (or both) similar to that seen in EBV hepatitis ( observations). Cytomegalovirus inclusions are not usually in such cases. Differentiation from rejection and lymphopro disease associated with EBV may be difficult and is based on FIG 57. microscopic examination and immunohistochemical stains to A, the HSV and the VZ virus produce viral antigens. The clinical profile and various hematologic p similar lesions in the liver allograft, ters are also helpful. characterized by large areas of coagulative-type necrosis (arrows). B, Recently, CMV has been implicated in the pathogenesis of the 46 multinucleated cells may be seen at the ishing bile duct syndrome (VBDS). ° Compatibility between the periphery of the lesion, and occasionally nor and recipient at the DR MHC locus, along with mismatclt, characteristic Cowdry type A inclusion at the class I locus and CMV infection have been identified as bodies are identified like those shown in dependant risk factors for the development of bile duct loss C (arrows). The Cambridge group has suggested that MHC-restricted presentation of viral antigens or mismatched class I MHC by DR-compatible bile duct cells is responsible for this 460 tion. occasionally present. Immunoperoxidase stains for various viral confirm the diagnosis when the pathologist is unsure on Herpes Simplex and Varicella-Zoster Hepatitis basis of the hematoxylin-eosin stains alone. / Both subtypes of HSV (1 and 2) and the VZ virus have been tied as causes of liver allograft hepatitis. Signs of graft have been seen as early as 3 days after transplant and may Virus 144 354 484 I:;t:: uca•ces of primary infection or reactivation of the EBV after any time thereafter. ' ' The clinical presentation with the 4 run the gamut from an infectious mononucleosis includes fever, fatigue, and body pain combined with serologic as seen in the general population 485 to severe life-threat 144 145 354 dence of hepatic injmy. ' ' Cutaneous manifestations lyrriphoproliferative disease similar to patients with the x- may not be present. With the VZ virus, allograft involvement lyrriphoproliferative disorder 486 or acquired immunodefi detected several days prior to the eruption of cutaneous syndrome (AIDS) .487 Lyrriphoproliferative tumors (B-cell lyrri typical of this disorder. Untreated, any of these viruses may have been seen with all kinds of transplantations but most 488 491 lead to massive hepatic necrosis. Therefore, early recognition in liver recipients 355 ' - and especially in infants and needle biopsy is particularly crucial since effective medical in whom the risk over the first 2 years after transplantation (acyclovir) is available. be as high as 10% .355 ' 492 The liver graft itself is frequently in Microscopically, all three viruses produce similar graft The most effective treatment measure for any of EBV syn 144 145 484 the 488 (Fig 57). ' ' They are characterized by circumscribed is discontinuance or reduct~onof immunosuppression, 493 to coagulative necrosis, showing no respect for the lobular antiviral therapy with acyclgvir should be added. Regres ture. Ghosts of hepatocytes intermixed with neutrophils and . of the syrriptoms; laboratmy( abnormalities, and lyrriphomas debris are seen in the center of the lesions. More .viab~ehepatocyte a:;ually, although •riot' invariably, fd}lows reduction of immunosup 488 490 491 are seen at the periphery, some of Which may c~IlJeyi.:t;i>grm f!t..<~:>.;, the ADV causes typical granulomas in the !lver. lmmunoperoxidase stains can be help if one cannot identify the inclusion bodies '(arrows). B, at the periphery of the granulo infected cells with intranuclear inclusions appear smudgy. (From Demetris AJ, Kaki zoe S, Oguma s: Pathology of liver transplantation, in Williams JW [ed]: Hepatic Trans plantation: Philadelphia, WB Saunders Co [in.press]. Used by permission.) staining to detect EBV viral antigens can be performed but frozen tissue. Immunophenotypic analysis of the infiltrative EBV-related disorders usually demonstrates a great non- T cells, whereas in acute cellular rejection, the T cells inate. Biopsy of enlarged lymph nodes (most common) or other HEPATITIS VIRUSES infiltrated by tumor is also used to establish the diagnosis of an related disorder. In the nodes, the changes vary from those with infectious mononucleosis 494 to a histology i TITIS B VIRUS 489 from immunoblastic lymphoma. Immunohistochemical and Viral hepatitis type B in the posttransplant period is restricted chain immunoglobulin gene rearrangement analysis are used to those patients who carried the virus prior to transplanta tablish the clonality of the tumors, if present.488- 491 although a few patients have acquired an infection, presumably Adenoviral Hepatitis a result of blood transfusion. Provision of a new liver usually, t not always, lowers the titer of the virus, as measured by the sur Allograft hepatitis due to the ADV has been restricted to antigen,496' 497 but return of the carrier state is almost univer- the pediatric population, although more recently an 502 In spite of this generalization, some chronic carriers have 356357 499 503 case in an adult has been identified. ' Adenovirus usually cnn<>Pontl" cleared the virus after transplantation - with passive curs within a very narrow time frame, namely, 20 to 30 days >phylaxis. In our experience, those chronic carriers who transplant, and the357 patients present with fever and elevated liver cleared the virus have been E antibody positive and E antigen jury test results. To date, almost all of the cases of ADV in tive, although this serologic profile is no guarantee that infec transplant population have been caused by viral subtype 5.357 will not recur. Among those recipients who become reinfected, ever, other viral subtypes (2, 11, and 16) have been associated small percentage will develop a carrier state and experience long hepatitis 495in the general population and could be expected to survival with minimal liver dysfunction. Recapitulation of the allografts. 357The diagnosis is made on needle biopsy chronic aggressive hepatitis jeopardized the recovery of the organ, after which immunosuppression should be temp ora 496 499501 stopped. · . of the recipients. - ' Delta agent co infection is an confounding factor and recurs along with the B vi 500 Histologically, granulomatoid collections of histiocytic cells .497' · 501 Reinfection of the allograft after tranSplantation for randomly located throughout the parenchyma (Fig 59). Hep fulminant hepatitis B is less certain, with several patients ex- necrosis may be detected but usually is less severe than that long-term survival with viral immunity.497' 498 The survival with HSV. Characteristic; "smudgy" intranuclear inclusions acute disease and fulminant hepatic failure has been accept identified in hematoxylin-eosin-stained sections, but experi"m although less favorable with chronic disease (Fig 60). required to be confident of the diagnosis without the use of In those who develop HBV disease after liver replacement, the on- stains. In infected cells, the chromatin is crowded toward the of symptoms usually occurs 6 to 8 weeks after transplantation. clear membrane, which imparts a muffin-shaped appearance to presentation varies from asymptomatic elevations of liver injury nucleus. Immunohistochemical stains are confirmatory. results to nausea, vomiting, jaundice, and hepatic failure. The syndrome, therefore, is not significantly different from viral '~l-lduusas seen in other immunosuppressed hosts. Serologic eval and needle biopsy of the graft confirm the diagnosis. Pathologic identification of acute hepatitis B as a cause of dysfunc rests on the recognition of preferential lobular alterations in the ~bsenceof significant inflammatory cell damage to bile ducts, arter 497 and venular endothelia. Hq~ever,the pathologic appearance ·HBV inthe allograft.is as varyed as the complete spectrum of hepatitis ~s;~een. in the general population hepatitis.:ip theliver allograft looks like 100 Jl------ 80 .... §: 60 ::;;: § (I) ~ 40 ACUTE HBV CHRONIC HBV 20 (HBsAg+)-e- (HBsAg+)~ 12 24 36 48 60 MONTHS AFTER TRANSPLANTATION FIG 60. Patient survival (life table method) after liver transplantation with cyclosporine-p for 65 adults with chronic 8 virus hepatitis compared with 13 adults with acute B virus atitis. viral hepatitis in other livers except for a relative paucity of mation in some cases, even with severe clinical manifestations FIG 61. pathologic changes. Hepatitis B virus infection of the allograft causes pathologic lesions similar to those seen in The natural history of hepatitis B infection of the allograft liver the general population and in other immunosuppressed hosts. In A there is an acute hepa becoming clearer. In our series of 59 patients who received titis with lobular disarray, hepatocyte ballooning, and necrosis. B, in chronic active B viral because of HBV disease, pathologic follow-up was available in 39 hepatitis in the allograft, a portal infiltrate with active piecemeal necrosis (arrow indicates 46 recipients who survived for more than 60 days. Thirty-four intact bile duct) (C, straight arrow) and preservation of the bile ducts (curved arrow) are these 39 patients had histologic evidence of recurrent hepatitis B the identifying features. D, the eventual outcome of many cases with chronic active hepa fection, disease, or both. titis after transplantation is graft failure or cirrhosis, which may occur with surprising rapid- A very typical sequence of pathologic changes was observed ity (see text). these specimens. The first evidence of recurrent hepatitis B was the detection of hepatitis B core antigen in the cytoplasm of transplant. A fifth patient rapidly became cirrhotic 147 days after patocytes several weeks after transplantation. Little liver replacement without any evidence of intervening chronic active change was detected at this time. Several weeks thereafter, mild hepatitis after transplantation. Follow-up of the few patients who ular disarray, hepatocyte swelling, and mild spotty acidophilic have apparently cleared the virus With no serologic or histologic ev crosis with regenerative change coincided clinically with the idence of recurrent B viral infection of the liver revealed nonspecific of elevated liver injury test results and signaled the development changes in three, non-B chronic active hepatitis in one and acute cellular rejection, which responded to bolstered immunosuppres disease activity. Most of the specimens at this time had the appetu~ ance of a mild acute hepatitis as seen in the general population sive therapy, in the remaining patient. cept for a relative paucity of lobular portal inflammation. It is not always easy for the pathologist to distinguish between re Follow-up of these patients over several weeks to greater than jection and hepatitis as a cause of p1alfunction. The most useful fea years revealed several clinicopathologic "syndromes." Six of the ture overall used to differentiate these two causes of malfunction is tients experienced a syndrome of unresolved lobular hepatitis, and the focus of lymphocytic damage./ The bulk of the injury associated five settled into a clinicopathologic profile resembling chronic carri., with acute HBVis directed at hep~tocytesand is recognized as lob ular .~u.t~I'liti()I1~·1~ute..ret~cfi()I1' ..on .the other hand, is directed at e.rs with little disease activity. Eighteen others d('lv~I<:m~P-;chronicac tive hepatitis, and four of these became cirrhotic"'J.;,5,J;:Q.,:5nMearsafter structures. within th.e portal tl'acts'. In chronic hepatitis, portal in- similar to the native organ. Later, features of chronic per flammation is present, and lobular alterations may be minimal. or active viral hepatitis are not uncommon (Fig 62). these cases, one has to determine if piecemeal necrosis or bile 10logically, in acute disease the diagnosis is based largely on destruction is the more prominent feature. It must be stressed lobular insult and is usually not difficult to differentiate from re an overall assessment of the entire biopsy specimen with careful . In chronic disease where the histologic appearance is that of amination of each portal tract must be performed. Individual persistence or active hepatitis, it may be hard to differenti may be quite difficult since both bile duct damage and from an indolent rejection reaction. It has been our policy that if piecemeal necrosis may be present. It has been our policy that is evidence of significant duct damage, rejection is considered significant amount of duct damage is detected, regardless of presence of piecemeal necrosis, a diagnosis of rejection made. ent.145 therapeutic or diagnostic clinical trial of immunosuppressive apy is then initiated. This approach seems prudent, considering fact that reductions of immunosuppression during hepatitis B A VIRUS tion may result in fulminant liver failure. Although fulminant hepatitis A virus has been an indication for replacement, it has not as yet been identified as the cause of dysfunction. Based on these observations, we expect that it NON-A, NON-B HEPATITIS appear quite similar clinically and histologically to that seen in Although precise identification of at least one of two .c.~..-.a,.."ftprllivers. responsible for non-A, non-B hepatitis has just recently achieved (hepatitis C),504 it is undoubtedly a cause of allograft titis.144' 145' 505 Episodes in patients with cryptogenic cirrhosis, PATHOLOGIST'S VIEW OF BILIARY TRACT those with unrelated disorders, and in patients who were thought TIONS have the disease prior to transplantation have been identified. It Anastomotic breakdown, necrosis, strictures, ascending infection, therefore be recurrent or develop de novo. The onset of 84 90 93 obstruction can affect the allograft biliary tree. - ' Although and laboratory abnormalities usually appear after 6 weeks. The complications are not uncommon in isolation, they often re- ical presentation is as variable as that seen in the general tion: mild asymptomatic elevation of liver injury test results to sive hepatic necrosis. Bone marrow aplasia, which also can cate milder attacks of non-A, non-B hepatitis not requiring transplantation, 506' 507 has been observed in children a few days weeks after liver replacement.508' 509 Four of the nine patients marrow aplasia survived, usually with slow recovery of the matopoietic system.508' 509 At present, the diagnosis is based on biochemical evidence of liver injury combined with the pathologic profile, although supporting serologic data may soon come available. The histopathologic appearance of presumed non-A-, non-B atitis may be as varied as that described for hepatitis B earlier. die biopsy specimens from patients thought to be infected the acute stages show mild Kupffer's cell hypertrophy, spotty philic necrosis of hepatocytes, and a relative paucity of infhumua tion. However, lobular disarray, mixed inflammatory cell FIG 62. , The histologic appearance of presumed noo-A. non-B viral hepatitis in the allograft is sim- hepatocyte ballooning, and .necrosis, which ·may be bridging, ilar to the type Bvirus.ln this case a chron(c active hepatitic lesion is seen. (From Deme also been seen. The .disease may also tris. AJ.~Katsizoi.S,,OgutnaS: Pathology(lfliver transplantation, in William JW [ed]: Hepatic fashion, as was experienced with two patients Transplat?tatiom.Phil.adelphia, WB Saunders Co[in press]. Used by permission.) the clinical profile and histologic am: fleet arterial pathology since the biliary tree is dependent solely the hepatic artery for its blood supply? 46 Most often the diagnosis biliary complications is made on the basis of clinical symptoms the results of radiologic procedures such as ultrasonography cholangiography (see previously).84- 90 In addition, during the postoperative period, most patients have a percutaneous T tube place that permits ready access to the biliary tree for radiologic cedures and assessment of bile flow. Needle biopsies are less useful than radiologic evaluations for diagnosis of large biliary tract disorders because of the relative specificity and insensitivity of early histologic findings.144' 145 ever, when access to the biliary tree is restricted, (late posttra period), biopsies may be more valuable as a screening tool. tract complications that have been recognized histologically· duct stricturing, obstruction, acute cholangitis, and biliary fistulas.144' 145 The histologic features of these complications identical to those seen in the nonallograft liver (Fig 63), which elude a predominantly neutrophilic portal infiltrate, p edema, intraepithelial and intraductal neutrophils, mild and cholangiolar proliferation, centrilobular cholestasis, and small clusters of neutrophils scattered the lobules. Although acute cellular rejection is included in FIG 63. pathologic differential, biliary tract disorders most commonly are The histologic manifestation of biliary tract· complications in the allograft are similar to sociated with a neutrophilic and eosinophilic portal those in nonallografted livers. The most important of these features is the neutrophilic pre whereas rejection shows a predominance of mononuclear cells dominance of the portal infiltrate in the absence of reactive biliary epithelial cell changes, the portal tracts. as shown in this case of acute cholangitis (A). When the biliary tree is obstructed, peri ductal edema accompanies the acute portal inflammation, and cholestasis is present in Recognition of biliary-vascular fistulas may be first noticed by the lobules (B). Fistulas between the biliary tree and the vasculature are recognized by the pathologist on needle biopsies and requires alertness to the presence of RBCs in bile ducts (C, arrow) or bile concretions in blood vessels (0, arrow). mal presence of RBCs in bile duct lumens or, conversely, bile (From Demetris AJ, Kakizol S, Oguma S: Pathology of liver transplantation, in William JW cretions in blood vessels (see Fig 63). Radiologic localization of [ed]: Hepatic Transplantation. Philadelphia, WB Saunders Co [in press]. Used by permis- abnormal communication, followed by corrective surgery or ,...,1-,...,,...."" sion.) plantation, is the usual course of events. DIFFERENTIAL DIAGNOSIS OF DRUG AND TOXIC INJURY Drug and toxic injury to the allograft liver are difficult to identity SEPSIS with certainty. The patients receive many potential hepatotoxic drugs and are subjected to other therapeutic maneuvers that may Infection of the blood, especially with gram-negative damage the liver. Therefore, if one strictly adheres to criteria for or can cause allograft dysfunction, which is usually manifested as gan specific toxicity, it is extremely difficult to incriminate any agent. dice. Histologic alterations are alsoobserved in the graft as a Regardless of these difficulties, erythromycin, prolonged peripheral of sepsis (endotoxemia) and are identical to those seen in Iluucu alimentation, high-dose steroidfi, and azathoprine have been lograft livers.510 These changes include cholangiolar , 144145 strongly suspected as causes allograft malfunction. ' One with bile plugging, acute cholangiolitis usually without cholangitis, of might. expect the allograft liver to? behave similar to nongrafted livers and hepatocanalicular cholestasis. Kupffer's cells are often hypertro in regard to ~rugtoxicities, unle~sCli1 MHC-restricted immunologic phied, and small clusters of neutrophils can be observed in the lob~. ules.144, 145 reaction.. is inyolw leukocyte antigen (HlA) or MHC compatibility been shown to either improve patient survival or reduce the on or incidence acute rejection in kidney511 and heart allografts.512 collected by Markus and associates concerning the role of HlA ,t..-.hina in liver transplantation were less clear cut.513 No patient was obseJVed for HlA compatibility. By contrast, a significant penalty in terms of survival was detected either the A, B, or DR locus was matched. Although rejection a cause of graft failure was more common when DR mismatching present, other causes of patient death or graft failure were even common when either class I or II loci were matched. Primacy of the new liver was particularly common in DR grafts. However, the diagnosis "primacy nonfunction" is of a wastebasket category, which often includes preseiVa- injucy, antibody-mediated rejection, vascular thrombosis, surgi misadventures, and cardiovascular instability in the donor or re Markus and associates suggested that MHC compatibility provide the ideal setup for recurrent disease since some of the 1ologic mechanisms important in the native diseases are to be MHC restricted.513 Alternatively, they suggested that alloresponse itself may be MHC restricted. Donaldson and col proposed a similar hypothesis.459 They found that DR d but A and/or B locus-mismatched grafts were more prone develop the vanishing bile duct syndrome (chronic rejection). suggested that induction of DR antigens on bile duct cells en these cells to act as antigen-presenting cells, presenting the tched class I antigens in an MHC-restricted fashion to recipi- effector cells. There are many possible explanations for the somewhat peculiar made with respect to HlA matching and liver allograft !'outcome. Like other allografts, livers seem to experience a lower in cidence of rejection when the DR \locus is matched. Paradoxically, does not auuear to. be a patient or graft survival advantage for DR or class I matching. This may be due to graft loss or death from causes other than rejection (e.g., technical mishaps infection). A higher incidence of recurrent native disease in matched patients may be a possibility, since cellular mechanisms are thought to play a prominent role in native CANDIDACY, ORIGINAL DISEASE, disease. This contrasts to most cardiac and renal diseases for transplantation is performed, where cellular immunity is AND OUTCOME strongly implicated. This argument is appealing because the mune damage purportedly mediated by T lymphocytes in liver eases such as hepatitis B is thought to be MHC restricted. the pathogenic mechanisms responsible for many native liver eases have yet to be elucidated. Furthermore, recurrent must be proved after liver grafting, which is not an easy task. spite of the diversity of etiologies, manifestations, and variability than to continue speculation, reanalysis of the data after technical problems with different diseases, the survival curves of a much larger patient population seems wise. not been greatly influenced by the original diagnosis with the of fulminant hepatic failure, chronic active hepatitis due 498 499 514 517 B virus, and liver malignancies (Fig 64). ' ' - These obser which have been extensively documented, are analogous to in renal transplantation where the original kidney disease has said to have little influence on the outcome. However, the foregoing summary is oversimplified, which could the value of information summarized in the following pages covers not only the influence of disease on outcome but also 100 80 ...., ~ 60 :::;;: § (/) '* 40 20 HEPATITIS B PRIMARY CANCER FULMINANT FAILURE OTHER -e-- -A- -EI- __._ 0 0 12 24 36 48 60 MONTHS AFTER TRANSPLANTATION nn<'ln<=:onof patient survival rates (life tablef method) after liver transplantation in adults cyclosporine-prednisone for HBsAG::positive postnecrotic cirrhosis (66 cases), .cancer (89 cases), fulminant hepatic failure (48 cases), and other nnnm,.finMnt indication$.tor LNER DISEASE TABLE 11. In the original efforts at clinical liver transplantation, 18 all of the Indications for Liver whose reason for transplantation was primary hepatic rna- Acute hepatic failure Postnecrotic cirrhosis 44 361 405 Alcoholic cirrhosis 113 113 Biliary atresias 236 5 241 Congenital hepatic 6 4 10 fibrosis -= Cystic fibrosis 3 4 7 Inborn errors of 75 52 127 metabolism Familial cholestasic 16 16 syndrome Neonatal (giant cell) 7 7 hepatitis Primary biliary cirrhosis 210 210 Seconda1y biliary cirrhosis 9 13 22 POSTNECAOTJC PRIMARY BILIARY PRIMARY SCLEROSING INBORN ERRORS Primary sclerosing CIRRHOSIS (HBsAg·) CIRRHOSIS CHOLANGITIS OF METABOLISM 4 99 103 __....._ cholangitis -&- -e- Budd-Chiari syndrome -- 2 21 23 12 24 36 48 60 Benign tumors 4 9 13 MONTHSAFTER TRANSPLANTATION Primary liver cancer 8 59 67 Bile duct cancer 18 18 Metastatic cancer 12 12 65. Liver trauma survival rates (life table method) after .liver transplantation using cyclosporine-ste 1 2 3 Secondary sclerosing 1 1 forthe r;najor indications in adults {18 ye~rsof age or older at the time they received cholangitis firl:lt transplant): Included are 296.cases qf postnecrotic cirrhosis (excluding HBsAG Total 438 1,031 of primarY biliary cirrhosis, 113 cases of alcoholic cirrhosis, - chqlangi\is;,and52 cases·ot inborn errors of metabolism. months, but the principal mortality has been between 6 and 36 (Fig 67). Small incidental malignancies that develop in cir livers usually do not recur, but extensive cancers recur in the of cases.527. 531' 534' 535 The results also are influenced by the '""~ cell type (Fig 68), presence of hilar lymph node metastases, 80 ' 67 499527531536 presence or absence of underlying liver disease. · · · · -- hepatoma, a slowly growing relatively uncom- "'-~ § 60 hepatocellular carcinoma with distinctive histopathologic fea- ::;;: § 537'538 is a "favorable" malignancy, and long survival has been Cl) 40 r.ompnsued even of patients with huge tumors that have invaded ?fi, diaphragm.67' 527' 531' 534' 539 Most authors have reported poor re with duct cell carcinomas, including the small K.latskin tumors 527530 532534 2j POSTNECROTIC BILIARY INBORN ERRORS PRIMARY are located high in the hepatic hilum, ' - ' but a recent CIRRHOSIS ATRESIA OF METABOLISM TUMORS 536 -e- -8- -+-- -A- experience has been more optimistic. Recurrence has exceptionally common in patients with conventional hepato 01---~----.---~---.----~---.--~----~------,,-~ 540 0 12 24 36 48 60 carcinomas.527 Epithelioid hemangioendotheliomas oc MONTHS AFTER TRANSPLANTATION an intermediacy position in that survival for at least 2531 years541 has achieved in more than one half of reported patients. ' to continue treating primacy hepatic malignancies is con FIG 66. Patient survival rates (life table method) after liver transplantation using cyclospo . It is difficult to resist continuing these efforts for the treat roids for the major indications in children (<18 years of age when they received thei of hepatic malignancies in carefully screened recipients, not transplant). Included are 235 cases of biliary atresia, 75 cases of inborn errors of because there is a chance of success but because there is so much olism, 44 cases of postnecrotic cirrhosis, and 8 cases of primary hepatobiliary information to be acquired about the biologic behavior of lignancy and who survived the perioperative period died withi" months of recurrent tumor. Smaller incidental malignancies 100 haved differently. The longest survivor in the world today her new liver at the University of Colorado on January 22, 1970 biliary atresia. The excised liver contained a 3-cm hepatoma. 80 little girl, 3 years old at the time of operation, will complete her "'-~ postoperative year in a few months. She is married to a United § 60 Marine and lives in Okinawa. The same observations with ::;;: 86 527 § malignancies have been made many times since_l ' Cl) 40 In spite of numerous disappointments, liver transplantation ?fi, means to extend resectability limits for hepatic neoplasms is still ing probed by many transplantation teams, often in comb 20 with adjuvant chemotherapy or other experimental treatment PRIMARY HEPATOMA INCIDENTAL HEPATOMA cols.528- 530 The percentage of tumor cases in large programs -e- -8- 514518519531 534 0 60 from 4% to 34% . ' ' ' - It has been about 5% at the 12 24 36 48 0 rado-Pittsburgh program (see Table 11). MONTHS AFTER TRANSPLANTATION Although strenuous efforts are made beforehand to rule metastases, a high rate of recurrence of all kinds of hepatic 67. nancies continues to be seen after total hepatectomy and survival rates for (life table method) after liver transplantation for primary hepato- plantation.* Metastases have had a tendency to home to the Mmn<>r<>rl with liver transplantation for nonmalignant diseases but with an liver.18' 531 Death from tumor recurrflnce has been reported as dij>covered on subsequent pathologic examination of 100 100 AZA PATIENTS CYA PATIENTS AZA GRAFTS CYA GRAFTS -e- -8-- __.,_ _...._ 80 eo ...., ...., § 60 § 60 5;: 5;: § § Cl) (/) 40 ~ 40 ~ 20 20 I BENIGN TUMORS EPITHELOID HEMANGIO- HEPATOMA BILE DUCT CANCER ENDOTHELIOMA METASTATIC TUMORS -e- -e.- -e- - __..._ 0~~---,--~-,--~--.-~---.--~~--~ 0 12 24 36 48 60 0 12 24 36 48 60 MONTHS AFTER TRANSPLANTATION MONTHS AFTER TRANSPLANTATION 69. FIG 68. ent and primary graft survival rates (life table method) after liver transplantation. One Patient survival (life table method) after liver transplantation for benign and mal red seventy recipients were treated with azathioprine (AZA) and steroids between mars that could not be treated by subtotal resection. Included are 13 patients with 1963 and February 1980 compared with 1,469 recipients treated with cyclosporine tumors, 54 with hepatocellular carcinoma, 18 with bile cancers, 8 with epithelioid and steroids between March 1980 and December 1988. Follow-up is complete gioendotheliomas, and 12 with secondary tumors originating outside the liver. 31 July 1989. these tumors and the influence on them of immunomodulation as low as 15 per million population 67 to as high as 200 per mil chemotherapy. Even a few patients with metastatic liver disease in an unpublished Canadian projection (Dr. Cal Stiller, personal 514 529 benefited from liver transplantation, • • 530 • 535 • 542 • 543 communication, University of Western Ontario, London, Ontario). when the primaries were neuroendocrine in origin.514 ' 535 • 536 In Based on these figures, and without a cap imposed by organ supply, remarkable case, a patient with multifocal liver metastases between 4,000 and 50,000 liver transplantations per year could be carcinoma of the breast was successfully treated with chemoth in the United States. Since there are no practical means of apy, autotransplantation of the bone marrow, and liver 529 artificial organ support analagous to renal dialysis, the waiting list of tion. Ultimately, she developed recurrences; further efforts at 530 recipients does not grow from year to year. plying this concept have failed. The variability of inclusion and exclusion factors of candidacy ac count for the wide-ranging estimates of need. Some of the earlier BENIGN DISEASE: THE POTENTIAL CANDIDACY POOL estimates were based on the assumption that patients with tu mors would be excluded, that the upper age limit would be 50 years, The criteria for case selection were blurred until 1980 because that patients with Laennec's cirrhosis or other "sin factors" would be mortality within the first postoperative year that exceeded 60% eliminated from candidacy, and that the list of applications would 69). It was impossible to tell for certain how much case not be as extensive as has proved to be the case. Furthermore, a was influencing results. When this was changed with the advent number of factors or diagnoses that precluded or strongly discour cyclosporine (see Fig 69), some issues of candidacy became aged transplantation 5 or 10 years ago are no longer absolute con In addition, with the better expectations and more general ·aindications, and some are no longer even questionable. ability of liver transplantation, the conceptual appeal of liver plantation was so great that this procedure became. the court of appeal for an astonishing number of patients withl~tha}hepatic there is a history of alco- ease. Estimates of yearly need for liver transplantation have 1:;.R~!;t~{;~.~~~7p'~~~~hto..Qbt~~ .c.o:ost,lltation with those who understand this disease. The objective is to of liver transplantation? Probably uncommonly, since endo abstinence after transplantation by arranging in advance for 552 sclerosis of varices is an effective alternative. In some pa care. In properly selected cases, Laennec's cirrhosis may be a with child's class A (good risk) cirrhosis, a distal splenorenal indication (see Fig 65) .544 Recidivism with alcohol use has been than 10%. might be the preferred way to relieve portal hyperten- We are using this approach in a small number of highly se- Older Age patients. However, it is important to emphasize that the liver itself decompresses portal hypertension through the An absolute upper age limit has been eliminated by aemon bed of the normal new liver. In patients who had variceal that recipients older than SO years have a similar 5-year survival were too sick to be considered for any operation younger adults.545 and who than transplantation, the 5-year survival after liver replacement far superior to that reported in series of generally better-risk pa Young Age or Small Size treated with shunting operation.553 The obvious limitations of The transplantation of very small infants, even in the newborn shunt approach to variceal bleeding has greatly reduced the fre riod of life, has become common, but the results are not as good 546 547 of portal diversion procedures in Western countries. with larger children. ' Other operations in the upper abdomen that were designed to complications of liver disease can create even more serious Portal Vein Thrombosis uult:;uls. Examples are procedures that disconnect venous collater- Although this was formerly a contraindication· to 548 549 going to lower esophageal varices and radical duct reconstruc tion, • ·the newly developed vein graft techniques (see Fig such as those used to treat sclerosing cholangitis or biliary routinely allow liver replacement in recipients who have (Kasai operation). hosed portal, splanchnic, or superior mesenteric veins.549 ' 550 As an alternative to these open operations, there has beengreater vein grafts are jumped from the superior mesenteric vein below of interventional radiologic or endoscopic procedures, such as transverse mesocolon, brought anterior to the pancreas, and of esophageal varices, and transhepatic duct stenting or for a portal anastomosis in the hepatic hilum. However, problem patients with previous shunts, duct . or other operations in the hepatic hilum should Multiple Previous Operations be denied transplantation for this reason. Although the trans Previous upper abdominal operations can complicate t operations are made more formidable, the results in experi tion enormously, particularly in patients with small cirrhotic hands can be almost as good as with a virgin operative that have extensive scarring of their inflow and outflow vessels obliteration of potential planes of dissection. The routine ment of liver size with imaging techniques helps to identity Chronic B Virus Carrier State 551 problem cases in advance. The portal vein is always studied It was ~ ~ ~ !I 1: HBigG prepared from the blood of immune donors. Seven pcultaJI syndrome resembling sclerosing cholangitis in a liver homo ~ 569 ~~ were treated with this monoclonal HBigG beginning preope~~+~. has been reported, but the same diagnosis has been or at the anhepatic phase of liver transplantation. 54 The first after transplantation in patients who had non-biliary tract ~ 144 ~ ent had reduction of surface antigen titer from very high to m.::><:;a.,e. There has been one report of recurrent autoimmune ~ detectable levels. In the second patient, the surface antigen level ~ undetectable for 5 months, after which it reappeared in low titer ~ the same time as core antigen was identified in the hepatocytes of Immunodeficiency Virus Carrier State ~II biopsy specimen that otherwise was normal. The half-life of this Whether patients with antibodies to HIV should be excluded from \ man monoclonal IgG was long enough to allow maintenance of candidacy is an unresolved issue. When screening tests for this dis 54 1 antibody excess with injections 2 to 4 weeks apart. Five ~n+~~-· ease became generally available in the spring of 1985, examples of 1 have been treated with larger doses, and all are free of HIV infections in kidney recipients were almost immediately re- ! after 2 to 7 months. It remains to be seen if the recurrent -n.nrotorl 571, 572 I pattern is appreciably altered by this kind of therapy. During late 1985, a massive study of the stored sera of 1,043 kid ~ Recipients who possess antibodies directed against the HBV ney, heart, or liver recipients treated between 1981 and 1986 was be I' face antigen have been free of hepatitis B virus following 573 gun at the University of Pittsburgh. Eighteen (1.7%) were found to II tation. However, it has been recently recorded that patients with be asymptomatic carriers. The liver recipients were most commonly human immunodeficiency virus (HIV) can regress from an affected. In about one third of the liver recipients, the HIV antibodies ently immune state, as defined by anti-B virus antibodies, to an were demonstrated in their sera, which had been collected and fectious carrier state, apparently by reactivation of residual virus 560 stored before the transplantation. Seroconversion after liver trans their immune system fails. Theoretically, the same thing could plantation occurred in the remaining patients, for a total incidence cur in a liver transplant recipient maintained on standard romHM of 2.6%. The liver allograft itself was a source of infection in a minor plant immunosuppression therapy. 5 574 ity of cases, 73, and most infections were attributed to blood com ponent therapy. Seroconversion still occurs at Pittsburgh,573 as well Non-A, Non-B Hepatitis as other institutions, despite the institution of screening enzyme im 144 505 575 576 Recurrence of non-A, non-B hepatitis ' has not been commoi munoassays in March 1985. • The low incidence of recurrence may merely reflect the difficulty Almost certainly the presence of HIV antibodies would have pre establishing the diagnosis. cluded candidacy if the diagnosis in the foregoing cases had been made in advance. As it turned out, these unfortunate victims of HIV Other Recurrent Diseases as well as 7 additional patients became available for long-term study The only other unequivocal example of disease recurrence under immunosuppression. 577 Eleven of these 25 recipients were in 498 499 561 562 been with the Budd-Chiari syndrome. ' ' ' This can be fected before transplantation, although this was not known until 561 563 vented with anticoagulation. ' An initial report of recurrence later in 8. The other 14 were infected perioperatively. Ten of the 25 primary biliary cirrhosis564 in three patients has recently recipients were infants or children. The organs transplanted were followed by an update on these patients and evaluation of 12 the liver (n = 15) and the heart or kidney (n = 5 each). After a mean primary biliary cirrhosis patients who have survived for more follow-up of 2.75 years (range 0.7-6.6 years), 13 recipients are alive. 1 year. A surprising percentage 565 of these long-term Survival is 7 out of 15, 2 out of 5, and 4 out of 5 of the liver, heart, and showed clinical and histologic evidence of recurrent disease. kidney recipients, respectively. The best results were in the pediatric groups have not been able to confirm these observations in group (70% survival), in which only 1 of 10 patients died of AIDS. In 447 566 568 series, ' - although the antimitochondrial antibodies contrast, AIDS caused the death of 5 of 15 adult recipients and was do not disappear after transplantation or else they reappear the leading cause of death. Transplantation plus immunosuppres 566 568 disappearing transiently. ' The reason for this discrepancy sion appeared to shorten the AIDSrfree time in HIV-positive patients not readily apparent, but it appears that cyclosporine may alter compared with nontransplant hemophiliac and transfusion control ease progression and histology of primary biliary cirrhosis affecurJ groups. Accidental accrual of HIV~positivetransplant recipients has either a native liver or allograft.565 Therefore, recurrences will slowed markedly since the systematic screening of donors, recipi bly not be severe or frequent enough to vitiate the value of ents, and blood,proAucts .. \JVilS. b.egun in 1985. However, patients plantation; · known to.he HIV:positive ..are.still bein~treated. It is clear that many patients can have prolonged benefit from transplantation in spite of having positive HIV test results. How use this information for decision making varies from center to ter. The most commonly accepted policy in the United States is screen all recipients but not to exclude transplantation solely cause of a positive HIV test result. If transplantation is TIMING OF TRANSPLANTATION the health care personnel must be protected from infection. It is miracle that none of the surgeons who operated on our patients the early 1980s without knowing the risk has (to our been infected. Screening of potential donors for HIV is obliga all centers, and a 50-minute test for this purpose has been 578 In the early days of liver transplantation, this therapeutic step scribed. The use of tests that identify the HIV antigens in add:.uuJ 579 seemed so drastic that it was as a last resort. What was to the antibodies 'may make donor screening more foolproof used then it presently is. defensible conservatism has become regressive today if the patient is allowed to deteriorate to the point of requiring life support systems before thinking of the transplant option. The rapidity of this deterio ration is highly variable. FULMINANT HEPATIC FAILURE The diagnosis of fulminant hepatic failure (FHF) can be made when there is sudden massive necrosis of a liver that previously has 580 582 functioned normally. - The term FHF has not been used for acute exacerbation of previously unrecognized chronic disease or for acute Wilson's disease. It was rarely treated with liver transplan tation before 1982.67 The results with transplantation has not been good enough to justify this drastic step for a disease syndrome from 580 582 which recovery might occur in 5% to 20% of cases. - Since then, FHF has been accepted as an emergency indication for transplanta tion in almost every liver transplant program worldwide. In several 583 591 large series, - the predominant diagnoses have been non-A, non-B hepatitis, B virus hepatitis, and toxic hepatitis from a variety of agents. Mushroom poisoning has been a much publicized toxic etiology.592 In our hands, the original diagnosis has strongly influ enced the outcome (Fig 70). The best results have been with B virus hepatitis. A decision to proceed with liver replacement often must be made in a few hours. The systematic collation of multiple parameters can help distinguish patients who have a good chance of recovery from 593 594 those who will die without transplantation. ' The etiology of the FHF may be an important prognostic determinant. 594 Premonitors of imm:irlent 'death include relentles~progression over a 7- to 14-day period, grade 3 or 4 encephalop*th:y, severe coagulopathy, rapid shrinlq~g~Qfth~J~yerasdoc:umentedwith imaging techniques, met 585 586 abow~·a<;ig:osi~r. : FIG 70. Patient survival (life table method) after liver transplantation in adults and children for /\GE CHRONIC DISEASE minant hepatic failure. Included are 9 cases of drug-related liver failure, 13 cases of B virus hepatitis, 31 cases of acute non-A, non-B hepatitis, 13 cases of acute h Ideally, a candidate for liver replacement should have an unequiv and 4 cases of fulminant hepatic failure of unknown etiology. need for transplantation but still be well enough to participate the complex process of recovery. A decision to go forward re time there is grade 4 encephalopathy and ventilator uvJJvuuo:;u"'"'' input from the primary physician, who may see gradually usually is too late. and often appalling social and vocational invalidism that If transplantation is performed before these grave findings, not be evident at first examination. The disability may be re livers with reversible lesions may be replaced unnecessarily. A in the loss of intellectual capacity with encephalopathic de biopsy after correction of the coagulopathy may provide decisive frequent hospitalizations for other complications of liver fail formation. If clotting cannot be corrected well enough to inability to function in a domestic environment, and arrest of closed needle biopsy, the patient can be explored with a new and development in infants and children. These issues of hand with the option of aborting the operation if the open of life loom large in most patients long before the truly termi looks favorable histopathologically. In spite of the pitfalls assu\Jia events of chronic hepatic failure. Formulas for candidacy based with liver replacement for FHF, current posttransplant survival liver function tests have not been helpful because the abnormal- 583 591 of 55% to 75% - compare favorably with the most in these tests are so variable from disease to disease or even projections of 20% for medical management alone. The results the same disease. Patients with cholestatic disorders (e.g., bil it certain that these efforts will continue. The perioperative atresia and primary biliary cirrhosis) usually become deeply frequently has been due to brain stem herniation during or just ,uuudiced with good preservation of hepatic synthetic functions for 520 525 557 transplantation, sometimes in spite of continuous monitoring of long time, ' ' whereas patients with hepatocellular disease tracranial pressure. Early referral to liver transplant centers, not be jaundiced in spite of th!=Jmost profound depressions in 548 tremely aggressive evaluation plus medical treatment, and an and prothrombin synthesi~. decision for surgical exploration with immediate transplantation The liability of procra,stinating tqolong before making a decision an option will be necessary to improve results. ·ansplant:ati9I1 hasyeHo,bedefilled. In one study in which 12% It will be unfortunate if the availability of transplantation ·· · .~~()~~,()fthe lost patients had ar too'far.towarcLliV:~JC;replacemei the therapeutic pendulum to swing iit!'l'P-tilat:P~S.<:tnd had GI. b,\f}.eding, coagulopathies, the hepatorenal syndrome, aspiration subacute bacterial peritonitis, or other end-stage complicauuJ 100 In another center, the mortality in patients considered too well placed on the active waiting list was greater than for those ad,.'"'''"" 80 to candidacy.597 When the mistake of underestimating disease ity with the supervention of a catastrophic complication is made, # Kaplan-Meier 60 • I , suscitation is sometimes successful. However, the outlook after ...... Mayo model ~ \ \ sequent transplantation is demonstrably degraded/ 98' 599 \ \ ·~ \ \ ',, ...... Group 1 40 ...... standing observations in a small group of pediatric liver mni~in~ ::J \ \ ______(/) \ that disease severity did not seem to influence pnctt .. ·:m \ \ ', Group 2 prognosis.600 20 \ ', Group...... 3 ... ___ ,... __ [_ ---r-----J The most precise studies of disease staging vs. posttransplantatic t '--r--- r outcome have been in adult patients with primary biliary 0 601602 601 sis. ' In the most recent of these investigations, disease 0 2 3 4 5 ity was defined with a formula in which age, serum bilirubin serum albumin level, prothrombin time, and edema severity Time, yr rately predicted life expectancy without transplantation. 603 overall survival in transplant recipients was greatly improved to these predictions (Fig 71). However, the patients who were influence of disease severity on the projected survival vs. the survival achieved with reasonable condition had a low perioperative mortality and a lantation. Group 1 patients were ·In the best condition and group 3 patients in the The prognosis without transplantation was worse in all stratifications, but so were survival of 80%; those with the most serious deterioration had a results after transplantation. This study quantified the penalty of undue procrastination perioperative mortality and a 2-year survival of only 55% (Fig re referral and treatment of patients with this disease. (From Markus BH, Dickson ER, The consensus in most centers is that transplantation should bsch PM, et al: N Eng! J Med 1989: 320:1709-1713. Used by permission.) considered at an earlier time before the stage of catastrophic plications is reached.604 Recently, an increasing number of patients with normal liver func and nonmalignant hepatic masses have had orthotopic trans for polycystic disease,217' 219 cystic hygroma,605 and ade 100 omatosis. The size of those lesions and the consequent disability life-threatening complications of the mass lesions were the indi 80 '\ for operation. The largest of the excised livers weighed ?ft. kg.605 60 ', ', Kaplan-Meier ~ ',...... ·~ .... Mayo model ::J 40 ...... QUESTION OF RETRANSPIANTATION (/) ...... ______ 20 Before the advent of cyclosporine, retransplantation was a rare ------Consequently, the graft and patient survival were almost syn 0 (see Fig 69). Almost immediately after the introduction of 0 2 3 4 5 attempts at retransplantation began to be made and enough success to warrant further such efforts.67 Now the pa Time, yr survival curves began to be 10% 1to 15% above the graft survival (see Fig 69), In the United States at the present time, approx FIG 71. one fifth of all liver grafts are(used for retransplantation. The Comparison of the projected survival in patients with primary biliary cirrhosis when for retta:hsplantation ·is oft~ne~tremely urgent, and many pa- with transplantation (Kaplan-Meier) vs. the expected outco.me with all alternative have a clini¢al 80 ...., RN ERRORS OF METABOLISM: § 60 S;: § A PANDORA'S BOX fl) 40 ~ 20 ONE GRAFT TWO GRAFTS THREE OR MORE GRAFTS -e- ---&- -e- Patients with liver-based inborn errors of metabolism can be 237 464 606 639 by providing a phenotypically normal liver. ' ' - It 0 12 24 36 48 60 recognized long ago and confirmed repeatedly since that the MONTHS AFTER TRANSPLANTATION 237 464 464 haptoglobin, ' and group-specific component, as 640 645 as other products of hepatic synthesis, - permanently re FIG 73. the original metabolic specificity of the donor after transplanta Survival of patients who required only one graft (1, 125 cases) is significantly better These observations made it virtually certain that liver trans 0.001) than for patients requiring two transplants (268 cases) or three or more (76 patients). would become a decisive way to treat the inborn errors of that resulted partly or completely from deficiencies of The success rate with retransplantation is only about one liver enzymes or from abnormal products of hepatic synthe that if a primary graft succeeds (Fig 73). The chances of 5-year . This expectation has been fulfilled in many patients for whom vival with a "take" of the first graft is about 75% (see Fig 73), s of as long as 18 years after transplantation are available twice as good as the expectation if two or more grafts are 12). With other disorders in which the pathogenesis was not This low success rate with retransplantation has caused understood, the transplantation itself became a powerful re question the probity of continuing these efforts. Yet, the salvage tool by showing the. extent of correction and by elucidating many patients whose first grafts have failed seems more than mechanisms by which correction was accomplished (see Ta- quate justification for what has been done. 12). In one patient, the opposite of a therapeutic correction was in that a coagulation defect present in the donor was con- If the option of retransplantation was foreclosed, it would 646 chilling effect on donor acceptance since the philosophy of d on the recipient. chance only would discourage the transplantation of grafts In the majority of these recipients, the inborn error had itself been more than minimal preservation times and would greatly tighten for damage to the liver, and a conventional indication of requirements for donor consideration. No liver transplant failure or the development of malignant tumors prompted the whom we are aware would countenance the concept of replacement. In these cases, the correction of the metabolic er- abandonment implicit in a policy that precludes or even was incidental. However, an increasing number of transplanta ages retransplantation in a patient who is potentially salvageable ' have been carried out solely for the purpose of correcting the error, and in many of these latter patients (see Table 12), the liver has been anatomically normal. Many inborn errors not correctable by liver transplantation can be 647 ~ffectivelytreated with allogeneic bqne marrow engraftment. De :ermining which kind of transplan\~tionwill be effective is crucial tabolic engin~~ringis considered. The guide 54 647 li~comeincreasingly clear. • TABLE 12. Inborn Errors Treated With Liver Transplantation Correction of Metabolic Longest Associated Liver Disease Explanation of Disease Defect Survival Disease Reference a 1-Antitcypsin Structural abnormality of the Yes 13 yr* Cirrhosis 606-609 deficiency protease inhibitor synthesized in liver Wilson's disease Abnormal biliary copper excretion, Yes 16.5 yr* Cirrhosis 606,610-616 decreased copper binding to ceruloplasmin, and copper accumulation in tissues; autosomal recessive gene mapped to chromosome 13 Fumaroylacetoacetate hydrolase Nearly complete 7.5 yr* Cirrhosis, 617-619 deficiency hepatoma 'JYpe Iglycogen Glucose-6-phosphatase deficiency Yes 7 yr* Glycogen storage, 620 storage disease fibrosis, tumors lV glycogen Amylo-1: 4,1 : 6-transglucosidase Incompletet 4.5 yr* Cirrhosis 606,612 tge disease !branching enzyme) defect fibrosis Unknown; pancellular disease, liver Not known 4.5 yr* Cirrhosis 621,622 often affected Sphingomyelinase deficiency, Not known 2 yr Idied) None 623 sphingomyelin storage Unknown, neurovisceral lipochrome No 7 yr* Cirrhosis 624 storage Hepatic ferrochelatase deficiency, Incomplete 1.5 vr Cirrhosis 625,626 ?overproduptive of 629 8 mo. None Peroxisomal alanine: glyoxylate Yes 630 aminotransferase deficiency 8 mo.* None Ornithine carbainoyltransferase Yes 631 deficiency None Yes 2.25 yr* Defective C protein synthesis None 632-635 Incomplete 6 yr* Low-density lipoprotein receptor deficiency, low-density lipoprotein overproduction Cirrhosis, a 636-638 Yes 4 yr* Factor VIII deficiency complication of blood component therapy Cirrhosis, a 639 Yes 6 mo. Factor IX deficiency complication of blood component therapy in University of Colorado-University of Pittsburgh series. Follow-up to January 1989. tArrwlopectin deposits found in heart biopsy 4 yr after transplantation. TRANSPLANTATION OF MULTIPLE ORGANS The increasing boldness with which hepatic transplantation has applied is evident from the many reports of transplantation of 17 219 648 651 liver plus kidney ' ' - and less frequently used combina 281 632 635 652 of the liver plus pancreas, liver plus heart, - ' and plus heart and lung.653 In these cases, the liver transplantation transplantation of the other organ have been done in disconti so that two standard procedures were performed in the same A different concept has been the inclusion of the liver in visceral clusters. The most complex operation of this kind has been of liver and pancreas plus the entire GI tract in two children with short-gut syndrome and secondary liver failure that developed 654 655 parenteral hyperalimentation. ' One of these grafts (Fig + delineation in embryonal life of that regi~nof the. Gl.tract (dark shaded) that was re sected in the organ clul?ter operation (E=.es.opnagus; LB =lung bud; L =liver; P =pan mars of the pancreas or duodenum with liver metastases (Fig 75), bile duct carcinomas with liver metastases, and a hepatoma that had invaded the duodenum and colori.657 The organs removed from the recipient in continuity have included the liver, stomach, pancreas, FIG 77. Completed reconstruction in the recipient. (From Starzl TE, Todo S, Tzakis A: Ann Surg 1989; 210:37 4-386. Used by permission.) FIG 75. The CT scan (top) of patient whose upper abdomen was filled with spindle cell sarcoma the time of operation. The tumor-laden liver is the structure to the left of the operating photograph (bottom). Most of the right half of the diaphragm was removed with the imen. The transverse colon is marked with white arrows. The margins were free of and none of the 38 lymph nodes studied had metastases. (From Starzl TE, Todo S, A: Ann Surg 19!39; 210:374-'386. Used by permission.) ,, ' alternative was developed in which the same resection was per l!i formed but only the liver was transplanted (Fig 78). Fifteen such pa tients have been so treated, but the follow-ups are too short to merit comment. This variation of the original cluster procedure has been developed as a more pragmatic operation but at the expense of ren dering the patient apancreatic. Malabsorption has been a serious clinical problem thus far, and thus it may influence cyclosporine doses. The day-to-day treatment of diabetes mellitus has not been difficult. If management of the iatrogenic diabetes mellitus proves difficult, pancreas transplantation at a more favorable moment re mains an option. FIG 78. This is an alternative to the reconstruction after an upper abdominal exenteration in which only the liver is replaced, This operation leaves the patient diabetic, but of 15 patients treated in this way, 13 are alive with follow-ups of several weeks to as long as 6 months. (From Tzakis A, Todo S, Starzl TE: Transplant Proc February 1990 [in press]. Used by per mission.) spleen, duodenum, proximal jejunum, and ascending plus trans-' verse colon (see Fig 74). The organs transplanted are shown in Fig ure 76. The completed recipient operation is shown in Figure 77. Of 15 such patients, 9 are alive after 6 to 14 months, 8 without ev idence of recurrent tumor. The ninth survivor may have stable pul monmy metastases. The majority of the survivors have been rehabil itated. This experience has illustrated how major components of the GI tract can be transplanted and has demonstrated how the use of organ clusters can allow extirpative procedures of a magnitude not previously imaginable. The major limitations of the cluster operation have been the diffi culty of finding appropriate organ donors, the difficulty of the oper ation, and the complexity of postoperative care. Considering the fact that of the organs being replaced, onl.y the liver is indispensable, an QUALITY OF LIFE Even in the early days of liver transplantation, the physical and decay caused by chronic liver disease could be stopped reversed in many of the recipients who survived chronically. most powerful determinants of their quality of life were the liver ion profile at the 1-year convalescent mark and the quantity of raids needed to maintain this function. 658 The adverse steroid in the quality of posttransplant life has been reduced since introduction of cyclosporine. Several studies have shown the re ble restoration of physical and emotional well-being that can 658 660 expected in infants and children, - including resumption of or even catch-up growth.661 Similarly, a recent group of adult liver transplant recipients stud objectively before and again Z years after operation demon broad improvement in social interaction, home management, the utilization of recl'eation and leisure time, and overall l.-llu"udal functioning. 662 A number of other findings were ob from these investigations. First, the severity of stress experi by the patient and the spouse after transplantation correlated with the ease of recovery. More than 90% of the recipi- who had a single transplantation state that they have no prob or only minor health problems 2 yeal's after transplantation. than 85% have returned to work and state that they are able to erform their jobs well. In contrast, the smaller number who re more than one transplant had a much poorer outcome, with 43% being able to work because of one or more disabilities. The follow-up of patients treated in the cyclosporine era dates to only 1980. However, a bellwether group of survivors remains 67 663 an original series of 170 patients treated from 1963 to 1979 . ' of these recipients are still living after 10 to 19 years. represented exactly one half of the survivors at 1 year. Only patients who were alive at 5 ye11rs died subsequently. One of the late deaths was caused by chronic/rejection 12.5 years after retrans •Plantation. The other death was from a lymphoma after 13.5 years. 663 l.ehabilitationhas he~ncompleteinthe long survivors. THE OPTION OF AUXILIARY TRANSPLANTATION With the auxiliary operation, as originally described in unmodified dogs/ the extra liver was placed in the right paravertebral gutter, rearterialized from convenient adjacent vessels, and provided with a portal venous inflow with systemic blood from the recipient iliac This is the kind of auxiliary liver transplantatiorvthat has permitted several long-term suc cesses. Note that the graft receives a portalfflow from the splanchnic venous system (S.M. Y.Ja()d .is dn:lined. .i()to the it:)feri()r ve()a <::;l\a (I, V.C:J. The principles of this operation 18 ·· · · · · :hi()w,an!i\.~pl.le~glle~.(From Starzl T.E [with the assis :i'! l:f(epfl;fi~Tta,[l~pl?,nta(ion.Philadelphia, WB Saunders vein or lower vena cava. The graft outflow was drained into the cipient inferior vena cava. It was observed that auxiliary grafts much more severely damaged than were orthotopically placed ers, primarily because of rapid hepatocyte atrophy.664 These effects could be prevented by diverting splanchnic venous PRACTICALUIMITATIONS through665 the auxiliary liver and away from the recipient's own er, suggesting that the splanchnic venous blood contained cific liver-supporting factors. The most important of these portal hepatrophic substances was proved to be insulin.325· 666 The condition of providing a splanchnic venous inflow to the Organ supply increasingly will influence candidacy criteria. How has been met in almost all of the subsequent clinical trials, which discussions about rationing transplant services for this reason 1978 numbered more than 50 (Fig 79).667 Auxiliary liver transplan premature since the balance between the need and supply of liv tion with unquestionable prolongation of life was first achieved has not been determined. In the United States, the yearly rate of the New York Memorial Hospital on December 13, 1972.668 The transplantations has reached approximately 1,600,673 averaging cipient, who had biliary atresia, still is alive with a follow-up of 669 per month between July and December 1988 (Dr. William than 16 years. In 1980, Roussin and associates in Paris reported United Network of Organ Sharing, personal communication, 29-month survival of an adult who was given an extra liver.670 1989). The annual European total is approaching this figure.674 patient was HBsAg-positive and died 8 years following Policies about organ donation will have to be reexamined if sub tion from a hepatoce1lular carcinoma in his host liver (H. further growth is to occur. Probably, many potential liver do personal communication, January 1989). nors are being rejected for inappropriate reasons. The arbitrary up With the increased success of orthotopic liver transplantation, per age limit for liver donors observed by most programs675 cannot terest in auxiliary transplantation waned. Very few further justified since the liver is the only organ that does not undergo were reported in the last decade.671 The resulting pessimism senescence.676 Atherosclerosis of its arterial supply usually is not been lightened by a recent report of the transplantation of whole found beyond the origin of the celiac axis.676 A limited experience ers or liver fragments to the right paravertebral gutter of six adult with livers from donors older than 50 years has been encouraging.677 cipients essentially as tried 672using the same operation that in Other potential donors of all ages often are excluded because of times. At the time of reporting with follow-ups of 5 to 23 poor blood gases, a need for inotropic or vasopressor drugs, minor all six recipients were alive. Cautious further trials undoubtedly abnormalities of liver function test results, or the existence of other be forthcoming. diseases such as diabetes mellitus.675 The results with such donors both in the United States161' 162 and Europe163 have been as good as with so-called perfect donors. The use of better preservation tech niques51-53 that allow safe storage of liver grafts for 1 day instead of the previous 6 or 8 hours should reduce organ wastage, since with this extra time, countrywide and worldwide networks of organ shar ing can be set up. ECONOMIC FACTORS The ability to pay for liver transplantation has had a profound in fluence on candidacy. Ironically, the feasibility first and then the practicality of liver transplantation were established without consid ering how to finance this revolutionary form of therapy. In 1983, a planning commission for the state~of Massachusetts estimated the average cost of liver transplantation in the first year would be $238,000,678 although the actual costs were only one third this high in a large program already in existence? 14 It is clear that as cal bills can be generated if patients are too disabled by the transplantation, if the first liver graft does not function well, serious complications develop, including the need for tion.114 Because of their fear of runaway expenses, many health carriers and government agencies have avoided financial REFERENCES bility to their679 constituents by classifYing liver transplantation as perimental" in spite of the Consensus Development conclusion to the contrary. The response to cost-conscious agencies is that liver transplantation can eliminate repeated pensive hospitalization of patients who are slowly dying 1. Welch CS: A note on transplantation of the whole liver in dogs. 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Schmid TH, Sandbichler P, Pernthaler H, et al: Multiple venous thrombosis ton, 1970, val III, pp 282-298. with recurrence of Budd-Chiari syndrome after liver transplantation for 582. BernUau .J, Rl.leff~,BEmhamou JP!,Fulminant and subfulminant liver fail paroxysmal nocturnal haematuria. Clin Transplant 1989; 3:194-197. definiti(lr1;¥IdcapSefhSemin Liver Dis 1986; 6:97-106. 583. Iwatsuki S, Esquivel CO, Gordon RD, et al: Liver transplantation for fulmi O'Grady 1, Williams R: Present position of liver transplantation and its im nant hepatic failure. Semin Liver Dis 1985; 5:325-328. pact on hepatological practice. Gut 1988; 29:566-570. 584. Peleman R, Gavaler 1S, Van Thiel DH, et al: Orthotopic liver transplantation . Miller C, Mazzaferro V, Makowka L, et a!: Orthotopic liver transplantation for acute and subacute hepatic failure in adults. Hepatology 1987; for massive hepatic lymphangiomatosis. Surgery 1988; 103:490-495. 7:484-489. Starzl TE: Surgery for metabolic liver disease, in McDermott WV (ed): 585. Bismuth H, Didier S, Gugenheim 1, et al: Emergency liver transplantation Surgery of the Liver Boston, Blackwell Scientific Publications, 1986 pp 127- for fulminant hepatitis. Ann Intern Med 1987; 107:337-341. 136. 586. Stieber AC, Ambrosino G, Van Thiel D, et al: Orthotopic liver transplanta 607. Putnam CW, Porter KA, Peters RL, eta!: Liver replacement for alpha-1-anti- tion for fulminant and subacute hepatic failure. Gastroenterol Clin North trypsin deficiency. Surgery 1977; 81:258-261. Am 1988; 17:157-165. 608. Hood 1M, Koep LJ, Peters RL, et al: Liver transplantation for advanced liver 587. O'Grady 1G, Alexander G1M, Thick M, et al: Outcome of orthotopic liver disease with alpha-1-antitrypsin deficiency. N Engl J Med 1980; transplantation in the aetiological and clinical variants of acute liver failure. 302:272-275. QJ Med 1988; 69:817-824. 609. Esquivel CO, Vicente E, Van Thiel D, et al: Orthotopic liver transplantation 588. Ringe B, Pichlmayr R, Lauchart W, et al: Indications and results of liver for alpha-1-antitrypsin deficiency: An experience in 29 children and 10 transplantation in acute hepatic failure. Transplant Proc 1986; 18(suppl adults. Transplant Proc 1987; 19:3798-3802. 3):86-88. 610. Dubois RS, Giles G, Rodgerson DO, et al: Orthotopic liver transplantation 589. Brems 11, Hiatt 1R, Ramming KP, et al: Fulminant hepatic failure: The role of for Wilson's disease. Lancet 1971; 1:505-508. liver transplantation as primary therapy. Am J Surg 1987; 154:137-141. 611. Groth CG, Dubois RS, Corman 1, et al: Metabolic effects of hepatic replace 590. Emond 1C, Aran PP, Whitington PF, et al: Liver transplantation in ment in Wilson's disease. Transplant Proc 1973; 5:829-833. the management of fulminant hepatic failure. Gastroenterology 1989; 612. Zitelli B1, Malatack 11, Gartner 1C 1r, et a!: Orthotopic liver transplantation 96:1583-1588. in children with hepatic-based metabolic disease. Transplant Proc 1983; 591. Gallinger S, Blendis LM, Roberts E, et al: Liver transplantation for acute and 15:1284-1287. subacute fulminant hepatic failure. Transplant Proc 1989; 21:2435-2438. 613. Esquivel CO, Marino IR, Fioravanti V, et al: Liver transplantation for meta 592. Woodle ES, Moody RR, Cox KL, et al: Orthotopic liver transplantation in a bolic disease of the liver. Gastroenterol Clin North Am 1988; 17:167-175. patient with Amanita poisoning. JAMA 1985; 253:69-70. 614. Sokol RJ, Francis PD, Gold SH, et al: Orthotopic liver transplantation for 593. Christensen E, Bremmelgaard A, Bahnsen M, et al: Prediction of fatality in acute fulminant Wilson's disease. J Pediatr 1985; 107:549-552. fulminant hepatic failure. Scand J Gastroenterol1984; 19:90-96. 615. Rakela 1, Kurtz SB, McCarthy 1T, et al: Fulminant Wilson's disease treated 594. O'Grady 1G, Alexander G1M, Hayllar KM, et al: Early indicators of prognosis with postdilutional hemofiltration and orthotopic liver transplantation. in fulminant hepatic failure. Gastroenterology 1989; 97:439-445. Gastroenterology 1986; 90:2004-2007. 595. Sinclair SB, Greig PD, Blendis LM, et al: Biochemical and clinical response 616. Polson RJ, Rolles K, Caine RY, et a!: Reversal of severe neurological manifes of fulminant viral hepatitis to administration of prostaglandin E. J Clin In tations of Wilson's disease following orthotopic liver transplantation. Q J vest 1989; 84:1063-1069. Med 1987; 64:244, 685-691. 596. Starzl TE, Gordon RD, Tzakis A, et al: Equitable allocation of extrarenal or 617. Fisch RO, McCabe ERB, Doeden D, et al: Homotransplantation of the liver gans: With special reference to the liver. Transplant Proc 1988; 20:131-138. in a patient with hepatoma in hereditary tyrosinemia. J Pediatr 1978; 597. Ghent CN: The liver transplant candidate: Assessment and followup, in 93:592-596. Maddrey W (ed): Transplantation of the Liver. New York, Elsevier North-Hol 618. Starzl TE, Zitelli B1, Shaw BW 1r, et a!: Changing concepts: Liver replace land, 1988, pp 59-86. ment for hereditary tyrosinemia and hepatoma. J Pediatr 1985; 598. Starzl TE, Iwatsuki S, Shaw BW 1r, et al: Analysis of liver transplantation. 106:604-606. Hepatology 1984; 4(suppl):47S-49S. 619. Van Thiel DH, Gartner LM, Thorp FK, et a!: Resolution of the clinical fea 599. Shaw BW 1r, Wood RP, Gordon RD, et al: Influence of selected patient vari tures of tyrosinemia following orthotopic liver transplantation for he ables and operative blood loss on six-month survival following liver trans patoma. J Hepatol1986; 3:42-48. plantation. Semin Liver Dis 1985; 5:385-393. 620. Malatack 11, Finegold DN, Iwatsuki S, et al: Liver transplantation for type I 600. Malatack 11, Schaid D1, Urbach AH, et al: Choosing a pediatric recipient for glycogen storage disease. Lancet 1983; 1:1073-1076. orthotopic liver transplantation. J Pediatr 1987; 111:479-489. 621. Cox KL, Ward RE, Furgiuele TL, et al: Orthotopic liver transplantation in 601. Markus BH, Dickson ER, Grambsch PM, et al: Efficacy of liver transplanta patients with cystic fibrosis. Pediatrics 1987; 80:571-574. tion in patients with primary biliary cirrhosis. N Engl J Med 1989; 622. Mieles LA, Orenstein D, Teperman L, et al: Liver transplantation in cystic 320:1709-1713. fibrosis. Report of 9 cases from the University of Pittsburgh. Lancet 1989; 602. Neuberger 1, Altman DG, Christensen E, et al: Use of a prognostic index in 1:1073. evaluation of liver transplantation for primary biliary cirrhosis. Transplanta 623. Daloze P, Delvin EE, Glorieux 1H, et;al: Replacement therapy for inherited tion 1986; 41:713-716. enzyme deficiency. Liver replacemeqt in Niemann-Pick disease type A. Am 603. Dickson ER, Grambsch PM, Fleming TR, et al: Prognosis in primary biliary J Med Gehet.1.977; 1:229"'-239. cirrhosis: Model for decision making. Hepatology 1989; 10:1-7. 624. Gartner JC:.Jr, Bc:li:gquuvi,.jWalatack 11, et al: Progression of neurovisceral 18Z storage disease with supranuclear ophthalmoplegia following 645. Hobart MJ, liver transplantation. Pediatrics 1986; 77:104-106. Med 1977; 146 625. Samuel D, Boboc B, Bernuau J, et al: Liver transplantation for protoporphy-~ 646. Dzik WJ, Arkin ria. Evidence for the predominant role of the erythropoietic tissue in pro from donor to toporphyria overproduction. Gastroenterology 1988; 95:816-819. 1987; 316:1217 626. Polson RJ, Lim CK, Rolles K, et al: The effect of liver transplantation in a 13 647. Parkman R: The 'transplantation to the treat- year old boy with erythropoietic protoporphyria. Transplantation 1988; ment of genetic 1378. 46:386-389. 648. Margreiter R, ommu.,d liver and kidney trans- 627. Wolff H, Otto G, Giest H: Liver transplantation in Crigler-Najjar syndrome. plantation. case report. Transplantation 1986; 42:84. 649. Gonwa TA, Nery im:ultaneous liver and renal trans 628. Kaufman SS, Wood RP, Shaw BW Jr, et al: Orthotopic liver transplantation plantation in :690-693. for type I Crigler-Najjar syndrome. Hepatology 1986; 6:1259-1262. 650. Rakela J, Kurtz Wilson's disease treateq 629. Watts RW, Caine RY, Rolles K, et al: Successful treatment of primary with -~n•..Jn•. .: ;orthotopic liver transplantation. Gas- oxaluria type I by combined hepatic and renal transplantation. 1987; 2:474-475. 651. Vogel W, 630. Todo S: Personal communication, 1989. hepatorenal 631. Casella JF, Lewis JH, Bontempo FA, et al: Successful treatment of homozy 652. Shaw BW Jr, gous protein C deficiency by hepatic transplantation. Lancet 1988 the heart 1:435-438. 653. Wallwork J, Transplantation of the liver, heart, and 632. Starzl TE, Bilheimer DW, Bahnson HT, et al: Heart-liver transplantation in lungs for and primary pulmonary hypertension. patient with familial hypercholesterolaemia. Lancet 1984; 1:1382-1383. Lancet 633. Bilheimer DW, Goldstein JL, Grundy SM, et al: Liver transplantation to 654. Starzl TE, al: Transplantation of multiple abdominal vide low-density-lipoprotein receptors and lower plasma cholesterol in viscera. JAMA child with homozygous familial hypercholesterolemia. N Engl J Med 655. Williams JW, SAA~iY::'lfN~lcF;'bsferPF, et al: Splanchnic transplantation-an 311:1658-1664. approach to thei~l!~l§'~ep¢hdenton parenteral nutrition who develops ir 634. Hoeg JM, Starzl TE, Brewer JB Jr: Liver transplantation for the treatment reversible liver dise!l~e?>JAMA1989; 261:1458-1462. cardiovascular disease: Comparison with medication and plasma exchan ., 5 656. Shaffer D, Maki T, DeMichels SJ, et al: Studies in small bowel transplanta in homozygous familial hypercholesterolemia. Am J Cardia/ tion. Prevention of graft versus host disease with preseiVation of allograft 59:705-707. function by dondr pretreatment with antilymphocyte serum. Transplanta 635. Mora NP, Cienfuegos JA, Ardaiz J, et al: Operative events in the first case tion 1988; 45:262-269. liver grafting after heart transplantation. Surgery 1988; 103:264-267. Starzl TE, Todo S, Tzakis A: Abdominal organ cluster transplantation for 636. Lewis JH, Bontempo FA, Spero JA, et al: Liver transplantation in a hemo the treatment of upper abdominal malignancies. Ann Surg 1989; philiac. N Engl J Med 1985; 312:1189-1190. 210:374-386. 637. Bontempo FA, Lewis JH, Gorenc TJ, et al: Liver transplantation in 658. Starzl TE, Koep LJ, Schroter GPJ, et al: The quality of life after liver trans philia A. Blood 1987; 69:1721-1724. plantation. Transplant Proc 1979; 11:252-256. 638. Gibas A, Dienstag JL, Schafer AI, et al: Cure of hemophilia A by 659. Starzl TE, Iwatsuki S, Malatack JJ, et al: Liver and kidney transplantation in liver transplantation. Gastroenterology 1988; 95:192-194. children receiving cyclosporin A and steroids. J Pediatr 1982; 100:681-686. 639. Merion RM, Delius RE, Campbell DA Jr, et al: Orthotopic liver transplanta 660. Zitelli BJ, Miller JW, Gartner JC Jr, et al: Changes in life style after liver tion totally corrects factor IX deficiency in hemophilia B. Surgery 1988; transplantation. J Pediatr 1988; 82:173-180. 104:929-931. 661. Urbach AH, Gartner JC Jr, Malatack JJ, et al: Linear growth following pedi- 640. Alper CA, Johnson AM, Birtch AG, et al: Human C3: Evidence for the liver as atric liver transplantation. Am J Dis Child 1987; 141:547-549. the primary site of ~ynthesis.Science 1969; 163:286-288. 662. Tarter RE, Erb S, Biller P, et al: The quality of life following liver transplan 641. Alper CA, Raum D, Awdeh Z, et al: Studies of hepatic synthesis in vivo tation: A preliminary report. Gastroenterol Clin North Am 1988; 17:207-217. plasma proteins, including orosomucoid, transferrin, alpha-1-antitrvns Iwatsuki S, Shaw BW Jr, Starzl TE: Five-year survival after liver transplanta C8, and factor B. Clin Immunol Immunopatho/1980; 16:84-89. tion. Transplant Proc 1985; 17:259-263. 642. Raum D, Marcus D, Alper CA, et al: Synthesis of human plasminogen by the 664. Starzl TE, Marchioro TL, Rowlands DT Jr, et al: Immunosuppression after liver. Science 1980; 208:1036-1037. experimental and clinical homotransplantation of the liver. Ann Surg 1964; 643. Wolpl A, Robin-Wino M, Pichlmayr R, et al: Fourth component of c-uu'l-''"' 160:411-439. (C4) polymorphism in orthotopic liver transplantation. Trans ment human 665. Marchioro TL, Porter KA, Dickinson TC, et al: Physiologic requirements plantation 1985; 40:154-157. for auxiliary liver homotransplantation. Surg Gynecol Obstet 1985; 121: 644. Wolpl A, Lattke H, Board PG, et al: Coagulation factor XIIIA. Transplantation 17-31. 1987; 43:151-153. 666. Starzl 'fE, Fr~cavillaA, Halgrimson CG, et al: The origin, hqrmonal nature, / and action of hepatotrophic substances in portal venous blood. Surg col Obstet 1973; 137:179-199. INDEX 667. Fortner JG, Yeh SDJ, Kim DK, et al: The case for and technique of topic liver grafting. Transplant Proc 1979; 11:269-275. B 668. Fortner JC, Kinne DW, Shiu MH, et al: Clinical liver heterotopic A transplantation. Surgery 1973; 74:739-751. Abdomen Bacterial 669. Starzl TE, Groth C, Makowka L: Clio chirurgica, in Landes RG (ed): sarcoma, CT of, 142 infections, 101-102 Transplantation. Austin, Texas, Silvergirl, 1988. upper, exenteration, reconstruction translocation, 101 670. Roussin D, Franco D, Berthelot P, et al: Heterotopic liver after, 144 Benign disease, 124-130 end-stage HBsAG positive cirrhosis. Lancet 1980; 1:990-993. ABO-compatible donors: Bile 671. Terpstra OT, Reuvers CB, Schalm SW: Auxiliary heterotopic liver perioperative immune events cancer, survival after liver tation. Transplantation 1988; 45:1003-1007. with, 57-60 transplant, 124 672. Terpstra OT, Schalm SW, Weimar W, et al: Auxiliary partial liver ABO-incompatible donors: duct tation for end-stage chronic liver disease. N Eng! J Med perioperative immune events after hepatic artery early clotting, 319:1507-1511. with, 60-63 47 673. Organ Donation is Increasing in the United States: United Network for Adenovirus necrosis, 48 gan Sharing update, 1989; 5:1-5. granuloma in liver due to, 107 plugs, cholangiolar, 55 674. Bismuth H, Ericzon BG, Rolles K, et al: Hepatic transplantation in hepatitis due to, 108 Biliary First report of the European Transplant Registry. Lancet 1987; 2:674- Alcoholic cirrhosis: survival after liver atresia, survival after liver 675. Darby JM, Stein KL, Grenvik A, et al: Management of the brain dead transplant, 121 transplant, 122 donor in the intensive care unit. JAMA 1989; 261:2222-2228. cirrhosis, survival after liver Alpha1 -antitrypsin deficiency, 138 676. Popper H: Hepatology, coming of age. Hepatology 1985; 5:1224-1226. Anaphylatoxins, 65 transplant, 121, 134 677. Teperman L, Podesta L, Mieles L, et al: The successful use of older Anastomosis(es) reconstruction, 34- 36 for liver transplantation. JAMA 1989; 262:2837. site formation, 30 gallbladder conduit, 678. Report of the Task Force on Liver Transplantation in Massachusetts. splenic artery to anomalous right Waddell-Caine technique for, Cross and Blue Shield, Massachusetts, May 1983. hepatic artery, 11-12 37 679. Starzl TE, Shapiro R, Teperman L: The point system for organ vessels, small, avoiding strictures, tract Transplant Proc 1989; 21:3432-3436. 34 complications, histologic 680. O'Donnell TF, Gembarowicz RM, Callow AD, et al: The economic _ Anomalies manifestations, 115 acute variceal bleeding: Cost-effectiveness implications for medical donor, 10-12 complications, pathologist's view surgical therapy. Surgery 1980; 88:693-701. hepatic artery, right, 11-12 of, 113-115 681. Evans RW: Cost-effectiveness analysis of transplantation. Surg Clin Antibody-mediated rejection: reconstruction, 1 Am 1986; 66:603-615. histopathology, 62 Bilirubin: in cholangiolar bile plugs, 55 682. Williams JW, Vera S, Evans LS: Socioeconomic aspects of hepatic Biloma a 1 -Antitrypsin deficiency, 138 tation. Am J Gastroentero/1987; 82:1115-1119. Aorta drainage with catheter, 46 683. Brass A: Surgery runs amok. Med J Aust 1984; 141:330. cold fluid into, 9 formation within dearterialized 684. Starzl TE: Liver transplantation in Australia. Med J Aust 1987; 147:369. crossclamping of, 143 liver, 46 685. Sheil AGR, Thompson JF, Gallagher ND, et al: Initial report of the Aortic infusion Biopsy National Pilot Liver Transplantation Programme. Med J Aust for core cooling of liver, 10 back-table, 44 147:372-380. of UW solution, 143 liver, before and after FK 506, 81 686. Lynch S, Kerlin P, Wall D, et al: The Queensland liver transplant Arteries reperfusion, hepatocellular necrosis gramme: The first two years. Med J Aust 1987; 147:380-385. grafts, posterior routes, 15 in, 54 687. Teperman L, Scantlebury V, Tzakis A, et al: Liver transplantation in hepatic (see Hepatic artery) Blood: formation of hepatocytes, 53 recipients: Pittsburgh. Transplant Proc 1989; 21:3963-3965. interlobular, deformed pattern, 52 Budd-Chiari syndrome, 128 mesenteric (see Mesenteric artery) Bypass, vena-venous, 20-23 splenic, anastomosis to anomalous pump-driven, 20 right hepati? artery, 11-12 Atresia: biliary, survival after liver c Cancer (cont.) "rogue," FK 506 and cyclosporine, Cytokines: activated by endotoxin, F hepatobiliary, survival after liver 79 65-66 Fat: lysed hepatocytes transplant, 119, 122 CMV (see Hepatitis, cytomegaloviral) Cytomegaloviral (see Hepatitis, Fatty vacuolization: hepatocellular, survival after liver Cold cytomegaloviral) 53 transplant, 123 fluid into aorta, 9 Fibrin deposition, 44 liver, 121-124 ischemia, 49 Fibrosis: cystic, 138 Candida, 48 preservation injury, 53 D Fistula: Eck, model Candidacy, 119-130 Colony-stimulating factor, 66 Dearterialized liver: biloma formation study; 75 potential candidacy pool, 124-130 Complement within, 46 FK 506, 76-84 Carcinoma: hepatocellular, survival 3a, 65 Development, 3-41 with cyclosporine · after liver transplant, 123, 124 Sa, 65 Diagnosis, differential kidney Carrel patch, 143 Computed tomography: of abdominal ~'rogue, of drug injury, 115 Catheter: for biloma drainage, 46 sarcoma, 142 of graft dysfunction, 85-99 liver Celiac axis: folded with origin of Conduit biliary reconstruction: with of toxic injury, 115 liver superior mesenteric artery, 13 gallbladder, with study Cell(s) Waddell-Caine technique, 37 Donor(s) ABO-compatible, perioperative Fungal· infectiom Connective tissue: necrosis, 48 endothelial, denudation, 53 immune events with, 57-60 Kupffer's cell hypertrophy, 103 Cooling ABO-incompatible, perioperative C5a, 65 core immune events with, 60-63 Children hypothermia and, 4-6 of liver with aortic infusion, 10 anomalies, 10-12 liver transplant cadaveric, total midline incision for, indications for, 120 for multiple organ procurement, survival rates, 73, 122 6-7 7 situs inversus, reconstruction after initial, 4-12 hepatectomy, 4-12 non-heart-beating, liver transplant to, 39 perfusion after, ex vivo, 13 procurement in, 7-10 Cholangiolar in situ Drug injury: differential diagnosis, bile plugs, 55 first technique, by extracorporeal proliferation, 55 hypothermic perfusion, 5 115 Cholangiolitis: acute, 55 principle of, 8 Cholangitis liver, 9 after liver transplant, 47 Core (see Cooling, core) E sclerosing, survival after liver C protein deficiency, 139 Eck fistula model: for cvc1osPOJJU1 transplant, 121 Crigler-Najjar syndrome, 139 study, 75 Choledochocholedochostomy: with T Crossclamping, 27 Economic factors: limiting tube stent, 1 of aorta, 143 transplant, 151- Choledochojejunostomy, 1 CT: of abdominal sarcoma, 142 Embryonal delineation: Cholestasis: hepatocanalicular, 55 C3a, 65 region, 141 Cirrhosis Cut -down liver, 40 Endorphin, 66 alcoholic, survival after liver Cyclosporine, 73-76, 125 Endothelial cell: denuaat!On,:qq:::; transplant, 121 Eck fistula model for study of, Endotoxemia, 63-70 biliary, survival after liver 75 Endotoxin transplant, 121, 134 with FK 506 levels Laennec's, 125-126 kidney function and, 83-84 (in dog), 67-68 postnecrotic "rogue" clones and, 79 at end of anhepatic phase survival after liver transplant, 121, limitations of, 73-74 graft survival, 69 122 liver regeneration and, 74-76 soluble mediators activated b)'; survival rates after liver lymphocyte cultures and clonal 65-66 transplant, 119 expansion, 78 Epstein-Barr virus hepatitis, Clones with prednisone, 110, 119 105-108 cyclosporine-resistant, development -resistant clones, development of, Erythropoietic protoporphyria, 138 of, 78 78 Extracorporeal hypothermic expansion, lymphocytes and perfusion, 5 cyclosporine, 78 steatoSiS;,madr'ovesitular, 44 removal recipient, 23-26 Herpes simplex hepatitis, 104- Hepatic artery from above downward, 28 Hilar necrosis, 48 Intestinal decontamination: selective, from below upward, completion of, clotting, early, 47 Histiocyte: sea-blue histiocyte originating from superior 101 25 syndrome, 138 Ischemia, from below upward, technique, 24 mesenteric artery, 11 49-56 Histocompatibility: influence of, cold, 49 replacement (see Transplantation of alternative methods for, 12 117-118 warm ischemia time, 49 liver) right, anomalous, splenic artery HIV carrier state, 129-130 transplantation (see anastomosis to, 11-12 Homograft Transplantation of liver) thrombosis, 48 K hepatic duct, typical extrinsic Lymphocytes Hepatic duct: common, homograft, effect on, 35 Kidney cultures vascular, 12 typical extrinsic mass effect on, function, cyclosporine and FK 506, clonal expansion of cyclosporine, 35 washing out, technique, 32 83-84 78 Hepatitis Human immunodeficiency virus transplant (see Transplantation of technique, 77 A virus, 113 carrier state, 129-130 kidney) interleukin 2 and, 77 acute, 132 Humoral rejection (see Rejection, Kupffer's cell hypertrophy, 103 Lymphocytosis: sinusoidal, and adenoviral, 108 hyperacute) Epstein-Barr virus, 106 B virus, 109-112 Hypercholesterolemia: familial, 139 Lysed hepatocytes: releasing fat, 44 acute, 132 Hyperoxaluria: type 1, 139 L chronic, carrier state, 127-128 Hypothermia: and core cooling, 4-6 Laennec's cirrhosis, 125-126 chronic, survival after liver Hypothermic perfusion: Leukocyte(s) M transplant in, 110 extracorporeal, 5 adherent to hepatocytes, 53 Macrovesicular steatosis, 44 infection of allograft, 111 sludging, 44 Malignancy (see Cancer) cytomegaloviral, 102-104 Leukotrienes, 65 Mesenteric artery, superior I histologic features, 103 Life: quality of, 147 origin folded with celiac axis, 13 103 necrosis in, IL (see Interleukin) Liver right hepatic artery originating Epstein-Barr virus, 105-108 Immune events, perioperative, benign disease, 124-130 from, 11 herpes simplex, 104-105 57-70 biopsy before and after FK 506, 81 alternative methods, 12 non-A, non-B, 112-113, 128 with ABO-compatible donors, cancer (see under Cancer) Metabolism (see Inborn errors of acute, 132 57-60 cooling, 9 metabolism) histologic appearance, 113 with ABO-incompatible donors, core, with aortic infusion, 10 Microvascular injury, 49 opportunistic viruses, 102 60-63 cut-down, 40 Model: Eck fistula, for cyclosporine varicella-zoster, 104-105 endotoxemia, 63-70 dearterialized, biloma formation study, 75 viral, allograft, clinicopathologic Immunosuppression: due to rat liver within, 46 Mucocele: formation prevention, 36 features, 102-108 transplant, and tolerance disease Multiple organ(s) viruses, 109-115 induction, 86-87 end-stage chronic, timing of liver procurement Hepatobiliary cancer: survival after Inborn errors of metabolism, transplant in, 133-135 core cooling for, 6-7 liver transplant, 119, 122 137-139 severity and projected survival, in situ cooling for, principle of, Hepatocanalicular cholestasis, 55 as Pandora's box, 137-139 135 8 Hepatocellular survival after liver transplant, 121, Epstein-Barr virus in, 106 transplantation of, 141-145 cancer, survival after liver 122 failure Multiple previous surgery, 126-127 transplant, 123 Indications: for liver transplant, 120 drug-related, 132 carcinoma, survival after liver fulminant, survival after liver Infant: very small, transplantation of N transplant, 123, 124 liver in, 126 transplant, 119, 132 necrosis in reperfusion biopsy, 54 Infections, 101-108 fulminant, timing of liver Necrosis Hepatocytes bacterial, 101-102 transplant in, 131-133 bile duct, 48 blood formation, 53 fungal, 101-102 function tests and FK 506, 81-82 connective tissue, 48 granuloma due to adenovirus, 107 in hepatitis, cytomegaloviral, 103 190 191 vascular; "medical" factors tumor necrosis factor, 66 ·. contributing· to, 49 Niemann-Pick disease,·138 Timing: of transplantation, 131-136 Prototype: of human question nt Tissue factor, 65 0 transplant,. 72-76 Revascularization: of graft, 30-34 Tolerance induction Pump-driven veno-venous bypass, Older age, 126 "Rogue" clones: FK 506 and effector pathways, 90-91 Organ cyclosporine, 79 immunosuppression due to rat Rubber: silicon rubber compound, 52 liver transplant and, 86-89 cluster operation, 141-145 Q inductive pathways, 89-90 multiple (see Multiple organ) Quality of life, 147 rejection and, 85-91 supply limiting liver transplant, 151 Tomography, computed: of Original disease, 119-130 s abdominal sarcoma, 142 Orthotopic liver transplant, 1 R Sarcoma: abdominal, CT of, 142 Toxic injury: differential diagnosis, Outcome, 119-130 Sclerosing cholangitis: survival after Recipient 115 liver transplant, 121 closure, 26 Transplantation of kidney Sea-blue histiocyte syndrome, 138 p crossclamping, 27 human prototype, 72-76 Shunt: portacaval, model for hemostasis for, 26 survival, 72 PAF, 65 cyclosporine study, 75 hepatectomy, 23-26 Transplantation of liver Perfusion Silicon rubber compound, 52 incision for, 19 auxiliary, option of, 149--'150 Sinusoidal endothelial cells, 53 ex vivo, after initial cooling, 13 operation, 18-41 candidacy, 119-130 hypothermic, extracorporeal, 5 Situs inversus: in child, modifications of standard potential candidacy pool, Perioperative immune events (see procedure, 38-41 reconstruction after transplant 124-130 to, 39 · Immune events, perioperative) Reconstruction cholangitis after, 47 Piggyback technique, 27-30 after abdominal exenteration, Sludging: leukocyte, 44 cooling (see Cooling) recipient vena cava preparation upper, 144 Slush development, 3-41 steps for, 29 preservation, UW solution for, biliary, 34-36 donor (see Donor) Platelet-activating factor, 65 14-18 gallbladder conduit, dysfunction, differential diagnosis, Portacaval shunt model: for Waddell-Caine technique for, techniques, 14 85-99 cyclosporine study, 75 37 Solutions Portal vein economic factors limiting, in multiple organ transplant, 143 test, characteristics and 151-152 graft from, antepancreatic, 33 constituents, 16 after transplant to child with situs function, early graft, 43-56 thrombosis, 126 UW (see UW solution) inversus, 39 graft syndromes vs. time after Prednisone: with cyclosporine, 110, Space of Disse: loss of, 53 Waddell-Caine (see Waddell-Caine transplant, 102 119 Splenic artery: anastomosis to technique) indications for, 120 Preexisting disease: early graft anomalous right hepatic artery, Rejection infection in (see Infections) function in, 43-45 11-12 acute cellular, 91-96 organ supply limiting, 151 Preservation, 12-18 Steatosis: macrovesicular, 44 histopathologic grading system, 95 original disease, 119-130 cold injury, 53 histopathology of, 93 Stent: T tube in orthotopic, 1 ex vivo perfusion after initial antibody-mediated, histopathology, choledochocholedochostomy, 1 outcome, 119-130 cooling, 13 Steroids, 125 62 in preexisting disease, 43-45 slush with cyclosporine, 121, 122 chronic, 96-98 preservation (see Preservation) techniques, 14 histopathologic features, 97 Swelling: of centrilobular hepatocytes, procurement (see Procurement) UW solution for, 14-18 clinicopathologic features, 91-99 55 vena cava, 27-30 in rat, unique properties, possible humoral (see hyperacute below) mechanisms underlying, inferior, 29 hyperacute, 57 87-88 Prevention: of rejection, 71-84 diagnosis, criteria for, 63 T Procurement recipient (see Recipient) of liver transplant in rat, early Technical failure, 45-49 reconstruction to child with situs liver, in non-heart-beating donors, histologic events, 91 7-10 Test solutions: characteristics and inversus, 39 prevention, 71-84 constituents, 16 rejection (see Rejection) tolerance induction and, 85-91 192 193 Transplantation of liver (cont.) preservation, 27-30 retransplantation (see recipient, preparation steps in Retransplantation) piggyback technique, 29 survival after one graft vs. survival retrohepatic, cleaning the after two or more grafts, 136 dissection, 31 survival rates, 73 Vena-venous bypasses, 20-23 technical failure, 45-49 pump-driven, 20 timing of, 131-136 Vessels tolerance induction (see Tolerance grafts, 14, 15 induction) homografts, 12 Transplantation of multiple organs, microvascular injury, 49 141-145 small, anastomoses, avoiding T tube: stent in strictures, 34 choledochocholedochostomy, 1 thrombosis, "medical" factors Tumor(s) contributing in, 49 benign, survival after liver Viruses transplant, 124 adenovirus (see Adenovirus) necrosis factor, 66 hepatitis (see under Hepatitis) Tyrosinemia, 138 HIV carrier state, 129-130 u w Ultrastructure: of endothelial cells, Waddell-Caine technique sinusoidal, 53 complications, 38 Urea cycle enzyme deficiency, 139 for gallbladder conduit biliary UW solution reconstruction, 37 aortic infusion of, 143 Washing out: the homograft, for slush preservation, 14-18 technique, 32 Wilson's disease, 138 v Vacuolization: fatty, of hepatocytes, y 53 Varicella-zoster hepatitis, 104-105 Young age, 126 Vein (see Portal vein) Vena cava z inferior, liver transplant piggyback onto, 29 Zoster-varicella hepatitis, 104-105