hepatopulmonary syndrome and liver

7/23/2019 Hepatopulmonary Syndrome and Liver

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LIVER TRANSPLANTATION WORLDWIDE

Hepatopulmonary SyndromeandLiverTransplantation(1) M arti nez G, Barbera JA, Navasa M , Roca J,

Vi sa J, Rodri guez-Roi si n R.Hepatopulmonarysyndrome associated with cardiorespiratorydisease. JHepatol 1999;30:882-889.(Reprinted with permission. 1999 EASL, theEuropean Association for the Study of theLiver.)

Abstract

Background/Aims: Hepatopulmonary syndrome is de-fined as a clinical triad including chronic liver disease,abnormal pulmonarygasexchangeresultingultimatelyinprofound arterial hypoxaemia, andevidenceof intrapul-monary vascular dilatation. Wereport fivepatientswithliver cirrhosis diagnosed with hepatopulmonary syn-dromewhohadassociatedchronic obstructiveor restric-tiverespiratory diseases.Methods:Clinical, radiographicand contrast-enhanced echocardiographic findings, and

systemic and pulmonary haemodynamic and gas ex-change,includingventilation-perfusiondistribution,mea-surements were assessed in all five patients. Resul ts:Echocardiography was consistent with the presence ofintrapulmonaryvasodilationwithoutintracardiacabnor-malities,andhighresolutioncomputedtomographic scanfeatureswerecompatiblewith clinical (3 cases) or histo-pathological diagnoses(2 cases) of associatedrespiratorydisorders. Themost commonprominent functional find-ingsweremoderatetoseverearterial hypoxaemia, causedbymoderatelytoseverelyincreasedintrapulmonaryshunt-ing and/or mild to moderate low ventilation-perfusionareas,andhypocarbiaalongwithincreasedcardiacoutputand alow pulmonary artery pressureand vascular resis-tance.Conclusions:Thesefunctional characteristics, clas-

sicallyreportedin thesettingofclinicallystable, uncom-plicated hepatopulmonary syndrome, conform to adistinctivelyunique,chronicgasexchangepattern.Equallyimportant, these pulmonary haemodynamic-gas ex-changehallmarksarenotinfluencedbythecoexistenceofchronic cardiorespiratory diseasestates. Thesedata mayhave clinical relevance for electiveindication of hepatictransplantation in patientswith life-threatening hepato-pulmonarysyndrome.

(2) Egawa H , Kasahara M , Inomata Y, Uemoto S,

Asonuma K, Fujit a S, Kiuchi T, H ayashi M ,

Yonemura T, Yoshi bayashi M , Adachi Y, Shapir o

JAM , Tanaka K.Long-term outcomeofliving-related liver transplantati on for pati entswith intrapulmonary shunting and strategyfor complicati ons. Transplantation1999;67:712-717. (Reprinted with permission.)

Abstract

Background:Of 320 livingrelated liver transplantationsperformedbetweenJune1990andSeptember1997, there

were21 livingrelated transplantationsfor patientswithintrapulmonary shunting, manifested by digital club-bing, cyanosis, and dyspnea. We report the long-termoutcome for more than 6 months and our strategy toovercome complications in these recipients. Pati ents: Atotal of21patients(agerange2-33years;19childrenand2adults;6malesand15females)wereclassifiedintothreegrades according to shunt ratio calculated by TcMAApulmonary scintigraphy; 5 in mild group (shunt ratio:less than 20%), 6 in moderated group (20%-40%), and10 in severe group (more than 40%). The originalunderlyingliver diseasewasbiliary atresia in all patients.Results: Spearmens correlation coefficient rank test re-vealedthat shuntratio correlatedsignificantly with PaO2in room air (P 0.0001), PaO2 in 100% oxygen (P 0.0004), hematocrit (P 0.0276),andperiodofdyspneabeforetransplantation(P0.023).Complications:Woundinfectionoccurredin 80,66,and80%,andbileleakagein20, 0, and 40% in mild, moderate, and severe groups,respectively. Patientswhohadportal vein thrombosisandintracranial complication wereclassifiedasseveregroup

and the incidence was 20 and 20%, respectively. Thepatientactuarial oneyear survival was80,66.7, and48%in mild, moderate, and severe groups, respectively, al-though there was no significant difference. All patientswhosurvivedimprovedhepatopulmonary syndromeandthe length of period required for the resolution wassignificantly correlated to the preoperative shunt ratio(P 0.023).Comments:Patientswith severeshuntingaresusceptibletowoundinfectionandbileleak.Thetrendofhigher incidence of portal thrombosis and intracranialcomplicationsin theseveregroupwascloselyrelatedhighhematocrit. Securesurgical techniquetoreducebileleakand delayed primary wound closure to reduce woundinfectionwerefoundtobeeffective.Anticoagulanttherapybyinfusingheparin through theportal vein followed by

Coumadin could prevent fatal portal vein thrombosiswithoutcounter riskoffatal cerebral hemorrhage.

Comments

Hepatopulmonary syndrome(H PS) ischaracterized byarterial hypoxemia caused by intrapulmonary vasculardil atati on that develops as a consequence of hepati cdysfunction. Thispulmonary vascular insult appearstotake at least two forms pathologically; diffuse precapil-lary/capillary dilatationsand intrapulmonary anatomicshunting caused by direct arteriovenous communica-tion. The syndrome most commonly develops in

association with any cause of portal hypertension orcirrhosis and thus is not infrequently recognized inpediatric and adult liver transplant centers.

Remarkably, each component of thissyndrome canbe eliminated with successful liver transplantationtechniques. Transplantati on of a cadaveric or li vingrelated l iver has resulted i n resolution of the vasculardil atati onsand normalization of arterial oxygen levels.These changes, however, may take months to occur,

Liver Transplantation, Vol 6, No 1 ( January), 2000: pp113-121 113


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suggesti ng that a significant remodeling occurs withinthe pulmonary vasculature once the normal venousblood consti tuents from the transplanted liver andportal system perfuse the pulmonary arterial bed.Thus, it appears t hat the pulmonary vessels, collec-

ti vely as an innocent bystander, appear to have asignificant vulnerabilit y to factors affected by hepati cfunction.1

Two recent articlesaddresspulmonary comorbidityand postliver transplantation mortali ty in patientswith HPS. Regarding comorbidity, Martinez et aldescribed additional pulmonary pathophysiology in 5of 16 adult pati ents (31%; age, 43 to 72 years) withvarying severity of HPS (PaO2 42 to 83 mm Hg,depending on patient posit ion). Using the sophisti -cated multipleinert gaselimination technique, routinepulmonary function testing, and high-resolution chestcomputed tomographic scanning, these investigators

reported that pati ents with well-defined HPScan haveother intrinsic pulmonary reasons for arterial hypox-emia that maynot bea consequenceof the li ver disease.More importantly, these other pulmonary insults (re-ported as expiratory airflow obstructi on, transbron-chial biopsy-proven usual interstiti al pneumonitis withtraction bronchiectasis, and necropsy-proven intersti-tial lung di sease associated with sarcoidosis) may notimprove after li ver transplantation. In such patients,the expectation of a normal PaO2 value after livertransplantation may never befulfilled. In addition, theexistenceof other intrinsic and nonvascular pulmonaryproblemsmay increasetherisk for postt ransplantation

morbidity. Recent experience at the Mayo Clinicsuggests a 20% incidence (5 of 25 patients) ofadditional clinically significant pulmonary problemsinpati entswith HPS; 4 pati entswereconsidered inappro-priate for liver transplantation because of those prob-lems (emphysema, idiopathi c pulmonary fibrosis, andbilateral bronchiectasis).

Concerning mortali ty, Egawa et al reported eightdeaths (days 19 to 260) after living related livertransplantation in 21 (38%) patients with HPS. Amortali ty of 16% (13 of 81 pati ents) was reported inthe largest li terature review (24 studies) published to

date.2

The conclusion from these seriesshould includethe fact that although complete resolution of HPS(even the most severe cases) can be realized as adramati c benefit of l iver transplantati on, such a resultis by no meansattainable without significant risk.

The report by Egawa et al also stressed the impor-tance of postoperative wound and biliary tract prob-lems and alluded to the possible importance of in-creased hematocrit (secondary to chronic hypoxemia)

in the development of life-threatening portal veinthrombosis. These investi gators also described thepotential prognostic importance of pretransplantati onquanti tative radionuclide lung scanning with brainuptake (greatest mortality risk for uptake 30%;

normal 5%).Regardless of the l iver transplantati on technique,profound hypoxemia associated with HPS(PaO2 50mm Hg) should beadditionally evaluated by completepulmonary function testing, high-resolution chest com-puted tomographic scanning, radionuclide lung scan-ning, and pulmonary angiography in highly selectedcases(poor responseto 100%inspired oxygen). Preli mi-nary data suggest that the use of technetium-labeledmacroaggregated albumin (99mTcMAA) lung scanningwith brain uptakei maging can specifically quantify thedegreeof hypoxemiaassociated with pulmonary vascu-lar dilatation and thereby separate various vascular

from nonvascular contri butions to hypoxemia i n pa-tientswith li ver disease.3,4

Although there is not a large experience thatcharacterizespoor outcomein pati entswith HPSafterliver transplantation, portal vein thrombosis, intracra-nial events, and multiorgan failure (associated withrefractory hypoxemia) appear to be associated withmortali ty. Specific complicationsassociated with livingrelated transplantation proceduresand theimportanceof hematologic responseto chronic hypoxemia deserveclosestudy.

The spectrum of outcome (mortali ty versus com-plete syndrome resolution) after liver transplantati on

emphasizes the importance of identi fying practical,diagnosti c strategies that address prognosis. HPS hasevolved from an absolute contraindication5 to rela-tive contraindicati on6 to indication for liver trans-plantation.2,7 This progress should not lull cliniciansinto thinking these cases are without irreversiblecomorbiditiesor i ncreased risk.

Michael Krowka, MDMayoClinic

200 First Street, SWRochester, MN 55905

References

1. Krowka MJ. H epatopulmonary syndrome and portopulmonaryhypertension: Di sti nctions and dilemmas. H epatology 1997:25:

1282-1284.2. Krowka MJ, Porayko MK, Plevak DJ, Pappas SC, Steers JL,

Krom RAF, et al. Hepatopulmonary syndrome with progressivehypoxemiaasan indication for liver transplantation: Casereports

and literature review. MayoClin Proc 1997;72:44-53.

Li ver Transplantati on Worldwi de114


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3. AbramsGA, NandaNC, Dubovsky EV, KrowkaM J, Fallon MB.Useof macroaggregated albumin lung perfusion scan to diagnose

hepatopulmonary syndrome: A new approach. Gastroenterology

1998;114:305-310.4. Whyte MKB, Hughes JMB, Peters AM, Ussov W, Patel S,

BurroughsAK. Analysis of intrapulmonary right-to-left shunt inhepatopulmonary syndrome. JHepatol 1998;29:85-93.

5. Van Thiel DH , SchadeRR, Gavaler JS, Shaw BW Jr, Iwatsuki S,Starzl TE. Medical aspects of l iver transplantation. H epatology

1984;41(suppl):S79-S83.6. Maddrey WC, Van Thiel D H. Liver transplantation: An over-

view. Hepatology1988;8:948-959.7. Internet: UNOSPediatric Policy3.6. 1998. http://www.unos.org

Cross-SpeciesTransmissionofPERV AppearsUnlikelyParadis K, Langjord G, Long Z, HeneineW,

Sandstrom P, Swi tzer W, et al. Search forcross-speciestransmission of porcine endogenousretrovirusin patientstreated with living pigtissue. Science1999;285:1236-1241.(Reprinted with permission. Copyright 1999American Association for theAdvancement ofScience.)

Abstract

Comments

Pig organshavebeen proposed to addressthe shortageof human donor ti ssuefor solid-organ transplantation,

cellular transplantation, and a handful of extracorpo-real t herapies. Human casereportsalready exist regard-ing the use of porcine tissue in extracorporeal liverperfusion2-4 and li ver transplantati on as a temporarysupport in fulminant hepatic failure.5 At least oneextracorporeal bioartificial liver containing porcinehepatocytes has completed preli minary (phase I) test-ing.6 However, reports of human cells infected by aC-type porcine endogenousretrovirus (PERV)7-9 raise

concernsregarding thepossibili ty of infectioustransmis-sion (pig to human) duringhuman exposureto porcinetissues. The recent report by Paradis et al1 providessome reassuranceon the safety of disease transmissionduring cross-species exposure between pig tissue and

humans. Specifically, this report suggested that thepotential risk for infecti on by PERV is small and didnot occur in the 160 patients tested.

C-type porcine endogenous retroviruses such asPERV havebeen recognized for nearly threedecades.10

Early reportsusing porcine kidney cellsasthe sourceofendogenousretrovirus suggested that theseretrovirusesdid not infect human cells.11,12 Only recently hasPERV infection been shown in vitro using human celllinesand sensitivedetection assays.7 At least threetypesof PERV are now recognized based on envelope genesequencing.13 The term PERV is used generally inreferenceto all three porcine endogenousretroviruses;

each share well-conserved sequencesin thepolreverse-transcriptase (RT) region.14 A substantial number ofcultured porcine cells have been shown to producePERV based on the presence of PERV RNA8 orporcine RT9 in their supernatant. These other porcinecells i nclude hepatocytes,8,15 lung,8 skin,8 endothe-lium,8 and peripheral-blood mononuclear cell s(PBMCs).9 Under in vitro coculture conditi ons, bothporcine endotheli al cells8 and porcine PBMCs9 havebeen shown to produce PERV capable of infecti nghuman embryonic kidney (HEK293) cells. In contrast,PERV obtained from cultured porcine hepatocytesdidnot produce sustained infecti on in HEK293 cells.15

The presence or absence of human fulminant hepati cfailureseradid not alter thesefindings.15

The possibili ty of PERV infecti on is significant forat least two reasons. First, PERV is an endogenousC-type retrovirus identified in nearly all pig t issues,16

alt hough apparently not in fetal brain cells.17 There-fore, the possibili ty of breeding PERV-free pigswouldbequite complex, if at all feasible.14 Second, PERV isaretrovirus and shares certain reproductive characteris-ticswith human immunodeficiency virustype1 (HI V-1). As a result, concerns of an acquired immunodefi-ciency syndromelike epidemic caused by PERV are

inevitable, alt hough no evidenceexistsregardingPERVasacausativeagent of human disease.Thepossibili ty of PERV infection into human cells

in vivo was the major focusof the retrospectivestudyrecently appearing in Science.1 These160 pati entswerestudied after exposureto avariety of porcine therapies,including extracorporeal liver perfusion (n 1),extracorporeal kidney perfusion (n 2), bioartificialliver perfusion (n 28), pancreatic islet transplanta-

Li ver Transplantation Worldwi de 115

Abstract not available


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tion (n 14), skin grafting (n 15), and extracorpo-real splenic perfusion (n 100). All therapies usedli ving porcine cells at the time of human exposure.Patientsranged in agefrom 2 to 77 yearsat thetimeofexposure. The durati on of exposure to porcine ti ssue

ranged from 15 minutes (extracorporeal pig kidneyperfusion) to 460 days (porcine pancreati c islet trans-plantation). The follow-up interval from treatmentranged from less than 1 day to 12 years (mean, 38months).

At least oneset of blood sampleswasobtained fromeach patient to obtain PBMCsand serum for analysis.Samples were analyzed in four laboratories usingmultiple recently developed assays specific for PERV:(1) polymerase chain reaction (PCR) for detection ofPERV DN A and pigD NA in PBMCs, (2) RT-PCRfordetecti on of PERV RNA in serum, and (3) proteinimmunoblot analysis for detecti on of antibodies to

PERV in serum. In some cases, samples of saliva werealso collected for detecti on of PERV RNA by RT-PCR.

PCR testing showed that the PBMCs of 125pati ents (81%) were negative for PERV DNA. Thisgroup included all 29 patients who had undergoneeither extracorporeal perfusion with a pig liver orporcine bioarti ficial liver. Of the 30 patients found tocontain PERV DNA in their PBMCs, 23 also con-tained other sequencesof pig DNA and werethereforeinterpreted asmicrochimeric. The23 patientsfoundtocontain microchimerism had undergone extracorpo-real splenic perfusion. The status of the remaini ngpatients was not interpretable because of insufficient

DNA for analysis. These PCR result s were supportedby screening assaysfor PERV antibodies and RT-PCRtesting for PERV RNA. None of the serum and salivasamples from these 160 patients, along with 5 closecontacts, contained PERV RNA. Four of 160 patientswere seroreactive to PERV Gag proteins, althoughnoneof the 4 patients had other molecular evidenceofPERV infection.

A small number of unexplained symptoms werenoted by pati ents exposed to porcine ti ssue. Threepati ents reported skin rashes after treatment with theporcine bioartificial liver. One of these patients also

reported a 4-day febrile episode that was otherwiseunexplained. An ongoing skin rash was noted in apati ent after porcine skin grafting. All PERV testi ngwasnegativein these4 patients.

A few weaknessesof thestudy areapparent, primar-ily because of its retrospective nature. For example,four separate laboratory sites were involved in sampleanalysis. As a result , similar tests were conducted withdifferent primers, antigens, and methods. To provide a

most conservative approach, posit ive results from anylaboratory resulted in an overall posit iveinterpretation.Even with thi s conservative approach, no examplesofPERV infecti on (in the absence of microchimerism)were detected. Of note, the study wasunable to detect

PERV infection in the sett ing of microchimerism.Another weakness of thi s study is the number ofsamples found to contain insufficient DN A to com-pleteanalysis(i.e., 5 of 160 for PERV DN A, 7 of 30forpig DNA). In some cases, samples were redrawn andanalyzed at a later date. Nonetheless, data frommulti ple patients were not interpretable because ofinsufficient DNA to rule out or establish microchime-rism. Thestudy isalso limited in that PBMCsweretheonly cell type examined. PBMCs were chosen partlybecauseof the easeof obtaining thesecellsand becauseof their potential importance in disease transmission.However, infection of cellsother t han human PBMCs

is a possibili ty not addressed in this study. A final,unavoidable weaknessof the study relates to the lowerli mits of detection of each assay. Namely, i t ispossiblethat samples reported as negati ve may have containedsequencesof PERV in numberslessthan thesensiti vityof the assay.

In summary, the possibili ty of PERV infection i nhumans remains unknown. The recent retrospectiveanalysis by Paradis et al1 provides further reassurancefor safety in proceeding with clinical testing of pigtissues as a treatment for human disease. Two smallerretrospectivestudiespreviously did not detect evidenceof PERV infecti on in patents after extracorporeal pig

kidney perfusion18 and porcine islet transplantati on.19

Well-designed prospective clinical trials are needed.Based on recent recommendations from the Food andDrugAdministrati on Advisory Panel on Xenotransplan-tation,20 these trials should include the analysis ofblood and serum from all patients exposed to liveporcine cells. State-of-the-art assays of three generalclassesshould beused to screen for PERV transmissionin these pati ents: (1) assays to detect PERV DNA inrecipient cells (preferably PBMCs) using PCR, (2)assaysto detect evidenceof viral infecti on by recipientantibody responses, and (3) assays to detect viral

expression in plasmaby enhanced RT-PCR techniques.This level of rigor is needed to ensure safety whenporcinecell s, ti ssues, or organsareused therapeuti callyin humans.

Scott Nyberg, MD, PhDMayoClinic

200 First Street, SWRochester, MN 55905



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References

1. Paradis K, Langjord G, Long Z, Heneine W, Sandstrom P,Switzer W, et al. Search for cross-speciestransmission of porcine

endogenousretrovirus in patients treated wit h living pig tissue.Science1999;285:1236-1241.

2. AbounaGM, Garry R, Hull C, Kirkley J, Walder DN . Pig-liverperfusion in hepatic coma. Lancet 1968;2:508-509.

3. Fox IJ, Langnas AN , Fristoe LW, Shaefer MS, Vogel JE,Antonson DL, et al. Successful application of extracorporeal

liver perfusion: A technology whose t ime has come. Am JGastroenterol 1993;88:1876-1881.

4. Chari RS, Collins BH, Magee JC, DiM aio JM, Kirk AD,Harland RC, et al. Treatment of hepatic failure with ex vivo

pig-liver perfusion followed by liver transplantation. N Engl JMed 1994;331:234-236.

5. Makowa L, Cramer D, Hoffman A, Breda M, Sher L, Eiras-

Hreha G, et al. T he use of a pig liver xenograft for temporarysupport of apatient with fulminant hepatic failure.Transplanta-

tion 1995;49:1654-1659.

6. WatanabeF, Mullon CJ-P, Hewitt W, ArkadopoulosN, Kahaku

E, Eguchi S, et al. Cl inical experience with a bioarti fical liver(BAL) in the treatment of severe liver failure: A phase I clinical

trial. Ann Surg 1997;225:484-494.

7. PatienceC, Takeuchi Y, WeissR. Infection of human cellsby anendogenousretrovirus of pigs. Nat Med 1997;3:282-286.

8. Martin U , Kiessig V, Blusch J, H averich A, von der Helm K,

Herden T, et al. Expression of pig endogenous retrovirus byprimary porcine endothelial cells and infection of human cells.

Lancet 1998;352:692-694.

9. Wilson C, WongS, Muller J, Davidson C, RoseT, Burd P. Type

C retrovirus released from porcine primary peripheral-bloodmononuclear cells infects human cells. J Virol 1998;72:3082-

3087.

10. Armstrong J, Porterfield J, De Madrid A. C-type virus parti cles

in pig kidney cell lines. JGenVirol 1971;10:195-198.

11. Todaro G, BenvenisteR, Lieber M, Sherr C. Characterization ofa t ype C virus released from the porcine cell line PK(15).

Virology 1974;58:65-74.

12. Lieber M, Sherr C, Benveniste R, Todaro G. Biologic andimmunologic properti es of porcine type C viruses. Virology

1975;66:616-619.

13. Takeuchi Y, PatienceC, MagreS, WeissR, BanerjeeP, LeTissierP, et al. Host range and interference studies on threeclasses of

pig endogenousretrovirus. JVirol 1998;72:9986-9991.

14. LeTissier C, StayeJ, Takeuchi Y, PatienceO, WeissR. Two sets

of human-tropic pig retrovirus. Nature1997;389:681-682.

15. Nyberg S, H ibbs J, H ardin J, Germer J, Platt J, Paya C, et al.Influence of human fulminant hepatic failure sera on endog-

enous retroviral expression in pig hepatocytes. Liver Transpl2000;6:76-84.

16. StoyeJ. No clear answerson safety of pigsastissuedonor source.Lancet 1998;352:666-667.

17. Weiss R. Xenografts and retroviruses. Science 1999;285:1221-1222.

18. Patience C, Patton G, Takeuchi Y, Weiss R, McClure M,

RydbergL, et al. No evidenceof pigDN A or retroviral i nfectionin patients with short-term extracorporeal connection to pig

kidneys. Lancet 1998;352:699-701.

19. Heneine W, Tibell A, Switzer W, Sandstrom P, Rosales GV,

Mathews A, et al. No evidence of infection with porcine

endogenous retrovirus in recipients of porcine islet-cell xeno-

grafts. Lancet 1998;352:695-698.20. Auchincloss HJ. Chairmans report from the Food and Drug

Administration Advisory Panel on Xenotransplantation, June3-4, 1999, Washington, DC. 14.

TransformingPower of Immunosuppression:Experimental MirageorClinical MirrortotheFutureH ojo M , M ori moto T, Maluccio M , Asano T,

M ori moto K, Lagman M , ShimboT, Suthanthiran

M .Cyclosporine inducescancer progression by acell-autonomousmechanism. Nature1999;397:530-534. (Reprinted by permissionfrom NatureVol. 397, pp. 530. Copyright 1999Macmillan MagazinesLtd.)

Abstract

Comments

In the practi ce of transplantation, most clinicians andsurgeons have had the unfortunate and disconcertingexperience of having a patient develop a malignancyposttransplantation, with rapid progression of thedisease. One clinical question emanati ng from theseobservations is always whether immunosuppressivedrugs themselves directly affect cell transformation.




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Theseissuesareespecially germaneto liver transplanta-ti on because this procedure i s oft en performed onpeoplewith mali gnant diseases. If specificimmunosup-pressiveagentsdirectly alter tumor biological character-istics, they likely will also impact on outcomeafter liver

transplantati on for mali gnant diseases. T his informa-tion isimportant for selecting thebest immunosuppres-siveregiment for thesespecific patient populati ons.

The report by Hojo et al1 attempts to answer thequesti on, does cyclosporine directly affect tumor biol-ogy?First, they directly evaluated theeffect of cyclospo-rine on the malignant phenotype in vitro by using anontransformed human pulmonary adenocarcinoma(A-549) cell line. Cells cultured in the presence ofcyclosporine (1 g/mL) showed anchorage-indepen-dent proli ferati on (an assay correlating with invasivetumor growth) and enhanced cell motil it y (an assay formetastases). Second, experiments were performed to

determine the effect of cyclosporine on the metastaticpotential of a cancer in vivo. M urine renal adenocarci-nomacellsshowed increased metastasesin immunode-ficient (SCID ) mice treated with cyclosporine (20mg/kg orally every other day). Theeffects were associ-ated with the ability of cyclosporine to increasetransforming growth factor- (TGF-) secretion bythe tumor cells and were blocked by monoclonalantibodies to TGF-. The data were interpreted tosuggest that cyclosporine can promote cancer progres-sion by direct effects on t umor cell s independent oftheir potential inhibit ion of immunesurveillance. Thisprovocativestudy, published in a high-impact journal,

raises several key questi onsgermane to the practiceofliver transplantation. T hese issues are discussed in thefollowing paragraphs.

Do the results of this study pertain to othercalcineurin inhibitors?The answer to this questi on isli kely. Tacrolimus, the other calcineurin inhibitor usedclinically, also increasesTGF- generation at clinicallyused concentrations.2 If theenhancement of themalig-nant phenotypeisTGF- mediated, then either cyclo-sporine or tacrolimusshould cause similar phenotypicalterations.

Can thesedatabeextrapolated to transplant popula-

tions? The answer to this question is difficult toaddress. First, the concentrati on dependence of thedata was not provided, and the concentrati ons ofcyclosporineused in thesestudiesaregreater than thoseused in clinical transplantation. Second, TGF- doesnot promote invasive behavior in all malignancies. Forexample, TGF- inducescell-cyclearrest and apoptosisin many hepatocellular carcinoma (HCC) cell lines.3

TGF- has even been suggested to be a tumor-

suppressor ligand.4 Despit e these observati ons, cyclo-

sporine has been shown to enhance the growth ofHCC cells and promote early recurrencein an animalmodel of transplantation for HCC, perhaps by aneffect independent of TGF-.5 These observations

make it likely that cyclosporine directly enhances themalignant phenotypein many solid tumors, including

HCCs.Should thisbasic study impact on how wepractice?

The answer isperhaps. First, thisstudy should not alterthe way pati ents are counseled regarding the risks ofimmunosuppression. Only skin cancer, lymphoma,cervical cancer, and Kaposis sarcoma appear to be

increased in li ver transplant recipients.6 These cancers,

aside from skin cancers, arerelated to viruses, and theironcogenesis is uniquely different from other solid-tissue mali gnancies. The most common solid-organtumors occurring in humans, breast, lung, and coloncancers, are not increased in this pati ent populati on,asidefrom patientswith ulcerativecolitiswho undergotransplantation for primary sclerosingcholangitis. Thesepatients are known t o be at high risk for colon cancerwith or without transplantation. In this respect, it isimportant to note that cyclosporine wasnot suggestedto promote tumor development in the study by Hojoet al,1 but only the invasiveness of established cancers.However, this study may alt er our choiceof immuno-suppressants when liver transplantation is performedfor malignant disease.

The importance of this issue is highlighted by the

recent availability of rapamycin asan immunosuppres-sive agent. Rapamycin is growth inhibitory for trans-formed cell lines and has recently been used success-fully as monotherapy in liver transplant recipients.7

Pil ot studies comparing a classic calcineurin inhibitorversus rapamycin after transplantation for mali gnantdiseaseareneeded to answer thisquestion in the era ofevidence-based medicine. However, it is possible thatrapamycin will become the agent of choice for thesepatients in the future, based on studieslike the one byHojo et al.1

In summary, I believethis study is a clinical mirrorto the future and not an experimental mirage. Wearenow approaching the era of selected immunosuppres-sion for different patient populations.

Gregory J. Gores, MDProfessor of Medicine

MayoClinic200 First Street, SW

Rochester, MN 55905



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References

1. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K,

Lagman M, et al. Cyclosporine induces cancer progression by acell -autonomousmechanism. Nature 1999;397:530-534.

2. KhannaA, CairnsV, Hosenpud JD. Tacrolimusinducesincreasedexpression of transforming growth factor-beta1 in mammalian

lymphoid aswell asnonlymphoid cells. Transplantation 1999;67:614-619.

3. Gressner AM, Lahme B, Mannherz H G, Polzar B. T GF-betamediated hepatocellular apoptosis by rat and human hepatoma

cellsand primary rat hepatocytes. JHepatol 1997;26:1079-1092.4. Tang B, Botti nger EP, Jakowlew SB, Bagnall KM , Mariano J,

Anver M R, et al. Transforming growth factor-beta1 isa new formof tumor suppressor with true haploid insufficiency. Nat Med

1998;4:802-807.5. Freise CE, Ferrell L, Liu T, Ascher NL, Roberts JP. Effect of

systemic cyclosporineon tumor recurrenceafter liver transplanta-tion in a model of hepatocellular carcinoma. Transplantation

1999;67:510-513.

6. Penn I. Posttransplantation de novo tumors in liver allograftrecipi ents. Liver Transpl Surg 1996;2:52-59.

7. Watson CJ, Friend PJ, Jamieson N V, Frick TW, Alexander G,Gimson AE, et al. Sirolimus: A potent new immunosuppressant

for li ver transplantation. Transplantation 1999;67:505-509.

DiscountPricingandtheCostof LiverTransplantationShowstack J, Katz PP, Lake JR, Br own RSJr,

Dudley RA, Bell e S, Wi esner RH , Zetterman RK,

Everhart J.Resourceutil ization in livertransplantation: Effectsof patient characteristi csand clinical practice. JAMA1999;281:1381-1386. (Reprinted with

permission. Copyright 1999, American MedicalAssociation.)

Abstract

Comments

Liver transplantation remains one of the most expen-

sivesurgical proceduresperformed today.1,2 Asaresult,third-party payers, providers, and public policymakershave an acute interest in containing, i f not reducing,costs. Expense management is hardly a minor i ssue; i tisamajor concern.

To addresstheseissues, managed care organizationshave resorted to centers of excellence contracting andcase management.3-7 Based on the available evidence,their efforts have apparently been successful. In 1993,the actuarial firm, Mil liman & Robertson, esti matedthat the total first-year charges associated with li vertransplantation were $302,900.8 By 1996, this figureincreased to $314,500.9 However, in their most recentreport, M il liman & Robertson indicated that the totalfirst-year charges for li ver transplantati on have de-creased significantly to $244,600.10

Unfortunately, most studiesconcerning the cost ofliver transplantati on haveactually focused on nonstand-ardized billed charges, which often bear li ttle relation-ship to actual accounting costs. This issue has beenaddressed at length in the li terature.11,12

In an exceptional effort to overcome many of theproblems associated with previous analyses of li vertransplantation costs, Showstack et al,13 in a three-center analysis, used a standard price list to value

resource utili zation. Although their analysis excludedall professional fees, they were able to examine inexquisit e detail the initi al transplantation hospitaliza-ti on for 711 pati ents who were aged 16 years or older,had nonfulminant liver disease, and for whom the liverwas the only organ transplanted. Multivariate modelswere tested in an effort to assess the i ndependentassociationsof resourceuti li zation with patient demo-graphic and clinical characteristics.




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The results of their analyses both confirm andelaborate on results previously reported.14-18 Resourceuti lizati on was typically greater for patients who weresickest at the time of transplantation, had alcoholicliver disease astheprimary diagnosis, received a donor

liver from a deceased person aged 60 years or older,died in the hospital, or received multi ple transplants.They also found significant differences in resourceuti lizati on acrosst hethreeparticipati ng centers.13

Based on their results, Showstack et al13 expressedconcern about recommended changesin theallocationof donor liverswithin theUnited States. Thesechanges,proposed by the Department of Healt h and HumanServices (DHHS) and recently endorsed by the Insti-tuteof Medicine, areintended to favor transplantationof the sickest patients first.19 Showstack et al13

correctly concluded t hat if these policies were imple-mented, therewill bea . . .substantial increase in the

resources used for liver transplantation in the UnitedStates.

The study by Showstack et al13 is eloquent inmethods compared with previous studies, althoughthey incorrectly characterized the result s of the Na-tional Cooperati veTransplantati on Study (NCTS).14,15

In the N CTS, which included surgical and otherprofessional fees, Evans et al15 clearly showed substan-tial differences in transplantati on procedurerelatedcharges and hospital length of stay according to avariety of demographic, prognosti c, outcome, andtransplant center characteristics. However, unlikeShow-stack et al,13 Evanset al15 did not perform multivariate

analyses.Showstack et al13 also indicatethat cost-effectiveness

has not been a serious consideration in the recentnational debate about organ allocation policies. Thisistrue in part, but i n public testimony presented to theDHHSat t heNational I nsti tutesof H ealth on Decem-ber 10, 1996, Evansand Kitzmann20 expressed concernthat the proposed D HHS policies would result in thepoorest transplant outcomes being achieved at thegreatest cost. In variouscontexts, offi cials representingthe United Network for Organ Sharing also haveexpressed similar concerns.

Ultimately, analyses such as that conducted byShowstack et al13 are of great significanceto transplantcenters in their efforts to manage costs. The reasonshould beobviousto most transplant center administra-tors. Managed care contracting based on global orpackagepricesrequiresacompleteknowledgeof actualcosts, resource utili zati on, and patient case-mix. Totheir credit, Showstack et al13 help usbetter understandeach of these. Unfortunately, at this ti me, most trans-

plant centers are unable to quanti fy these financialindicatorsin ameaningful way.

Increasingly, transplant centers are being forced toaggressively compete on the basis of price becauseoutcomes have become simi lar across centers.21-23 In

effect, providers are assuming risk relative to theirpatient-selection policies. As a result, in hopes ofremaining financially viable, it is likely transplantcenterswill becomemoreconservative in the pati entsselected for transplantation. They will eventually recog-nize the financial penalty associated with adversepatient selection. Thus, the highly controversial poli-cies proposed by the DHHS may in principle gainacceptance, but in clinical practice, their goal will notbeachieved.

Finally, note that the pricing policies of transplantcentersarehighly variablebased on the market penetra-tion of managed care. Thisis readily apparent i n Table

1. Clearly, transplant centers associated with hospitalsin highly managed care areas have a policy of aggres-sively marking up their hospital charges relative toactual costs, whereasthepoli ciesof transplant hospitalsin marketswith low-to-moderatemanaged carepenetra-tion are far more conservativein their pricing policies.Consequently, based on a fee-for-service mentali ty,transplant hospit als in markets heavily penetrated bymanaged care can offer deep discounts for the servicesthey provide, which is apparent from the grossdeduc-tionsfrom patient revenueslisted in Table1.

Table1. Overall Inpatient Hospital Experiencefor AllPatient Admissions, 1997

FinancialIndicator

Managed Care MarketPenetration*

High Moderate Low

Grosscharges($) 32,091 16,686 8269

Adjusted charges

($) 14,208 9461 3903

Reimbursement($) 7709 6683 3151

Cost ($) 5133 5077 2480

Margin ($) 2576 1606 671

Margin asa per-centageof cost

(%) 50 32 27

Grossdeductionsfrom revenue

(%) 46 29 19

*Definition of managed carepenetration: high, 59%; moder-ate, 35%; low, 11%.Case-mix and wage-index adjusted.



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Of course, in a market now based on contractedprices, actual accounting costs and markups becomemeaningless considerations for payers intent on mini -mizing the prices they pay for the services theirbeneficiaries require. Payers are not particularly con-

cerned about the alleged unprofitabil ity of academicmedical centers.24-27 They aremuch moreinterested inmaximizing the size of the discounts t hey negotiate,even when hospit als with lower markups may offerbett er prices. Thus, the solution should beobvious. Inthecurrent managed caremarketplace, hospitalsshouldaggressively mark up their prices, offer reasonably largediscounts, and thereby reap the benefitsassociated withhigh profitabil ity. M eanwhile, payers can remain disil-lusioned with their discount mentality.

Roger Evans, PhDMayoClinic

200 First Street, SW,Rochester, MN 55905

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M (eds). Clinical transplants1993. Los Angeles: UCLA TissueTyping Laboratory, 1994:359-391.

2. EvansRW. Effect of li ver t ransplantation on local, regional, andnational health care. In: Busuttil RW, Kl intmalm GB (eds).

Transplantation of the liver. Philadelphi a: Saunders, 1996:869-879.

3. Ascher NL, EvansRW. Designation of liver transplant centersinthe United States. Transplant Proc 1987;19:2405.

4. EvansRW. Public and privateinsurer designation of transplanta-

tion programs. Transplantation 1992;53:1041-1046.5. Dahlberg R. Centersof excellence. Managed CareQ 1997;5(3):

86-88.6. Albrecht GL, Fitzpatri ck R (eds). Advancesin medical sociology.

Caseand caremanagement. Stanford: JAI Press, 1995.7. Mayer GG. Case management as a mind set. Qual Manage

Health Care1996;5(1):7-16.8. Hauboldt RH. Cost impli cationsof human organ t ransplanta-

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12. Finkler SA. The distinction between cost and charges. AnnIntern Med 1982;96:102-109.

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li ver transplantation: Costs, insurancecoverage, and reimburse-ment. Gastroenterol Clin North Am 1993;22:451-473.

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Cecka JM, Terasaki PI (eds). Cli nical transplants, 1995. LosAngeles: UCLA TissueTyping Laboratory, 1996:315-322.

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after liver transplantation on resource uti lization. Arch Surg1997;132:1098-1103.

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