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Hepatopulmonary syndrome (HPS) is characterized by
arterial hypoxemia caused by intrapulmonary vascular
dilatation that develops as a consequence of hepatic
dysfunction. This pulmonary vascular insult appears to
take at least two forms pathologically; diffuse precapillary/capillary dilatations and intrapulmonary anatomic
shunting caused by direct arteriovenous communication. The syndrome most commonly develops in
association with any cause of portal hypertension or
cirrhosis and thus is not infrequently recognized in
pediatric and adult liver transplant centers.
Remarkably, each component of this syndrome can
be eliminated with successful liver transplantation
techniques. Transplantation of a cadaveric or living
related liver has resulted in resolution of the vascular
dilatations and normalization of arterial oxygen levels.
These changes, however, may take months to occur,
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114
References
1. Krowka MJ. Hepatopulmonary syndrome and portopulmonary
hypertension: Distinctions and dilemmas. Hepatology 1997:25:
1282-1284.
2. Krowka MJ, Porayko MK, Plevak DJ, Pappas SC, Steers JL,
Krom RAF, et al. Hepatopulmonary syndrome with progressive
hypoxemia as an indication for liver transplantation: Case reports
and literature review. Mayo Clin Proc 1997;72:44-53.
3. Abrams GA, Nanda NC, Dubovsky EV, Krowka MJ, Fallon MB.
Use of 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,
Burroughs AK. Analysis of intrapulmonary right-to-left shunt in
hepatopulmonary syndrome. J Hepatol 1998;29:85-93.
5. Van Thiel DH, Schade RR, Gavaler JS, Shaw BW Jr, Iwatsuki S,
Starzl TE. Medical aspects of liver transplantation. Hepatology
1984;41(suppl):S79-S83.
6. Maddrey WC, Van Thiel DH. Liver transplantation: An overview. Hepatology 1988;8:948-959.
7. Internet: UNOS Pediatric Policy 3.6. 1998. http://www.unos.org
Comments
Pig organs have been proposed to address the shortage
of human donor tissue for solid-organ transplantation,
cellular transplantation, and a handful of extracorporeal therapies. Human case reports already exist regarding the use of porcine tissue in extracorporeal liver
perfusion2-4 and liver transplantation as a temporary
support in fulminant hepatic failure.5 At least one
extracorporeal bioartificial liver containing porcine
hepatocytes has completed preliminary (phase I) testing.6 However, reports of human cells infected by a
C-type porcine endogenous retrovirus (PERV)7-9 raise
115
concerns regarding the possibility of infectious transmission (pig to human) during human exposure to porcine
tissues. The recent report by Paradis et al1 provides
some reassurance on the safety of disease transmission
during cross-species exposure between pig tissue and
humans. Specifically, this report suggested that the
potential risk for infection by PERV is small and did
not occur in the 160 patients tested.
C-type porcine endogenous retroviruses such as
PERV have been recognized for nearly three decades.10
Early reports using porcine kidney cells as the source of
endogenous retrovirus suggested that these retroviruses
did not infect human cells.11,12 Only recently has
PERV infection been shown in vitro using human cell
lines and sensitive detection assays.7 At least three types
of PERV are now recognized based on envelope gene
sequencing.13 The term PERV is used generally in
reference to all three porcine endogenous retroviruses;
each share well-conserved sequences in the polreversetranscriptase (RT) region.14 A substantial number of
cultured porcine cells have been shown to produce
PERV based on the presence of PERV RNA8 or
porcine RT9 in their supernatant. These other porcine
cells include hepatocytes,8,15 lung,8 skin,8 endothelium,8 and peripheral-blood mononuclear cells
(PBMCs).9 Under in vitro coculture conditions, both
porcine endothelial cells8 and porcine PBMCs9 have
been shown to produce PERV capable of infecting
human embryonic kidney (HEK293) cells. In contrast,
PERV obtained from cultured porcine hepatocytes did
not produce sustained infection in HEK293 cells.15
The presence or absence of human fulminant hepatic
failure sera did not alter these findings.15
The possibility of PERV infection is significant for
at least two reasons. First, PERV is an endogenous
C-type retrovirus identified in nearly all pig tissues,16
although apparently not in fetal brain cells.17 Therefore, the possibility of breeding PERV-free pigs would
be quite complex, if at all feasible.14 Second, PERV is a
retrovirus and shares certain reproductive characteristics with human immunodeficiency virus type 1 (HIV1). As a result, concerns of an acquired immunodeficiency syndromelike epidemic caused by PERV are
inevitable, although no evidence exists regarding PERV
as a causative agent of human disease.
The possibility of PERV infection into human cells
in vivo was the major focus of the retrospective study
recently appearing in Science.1 These 160 patients were
studied after exposure to a variety of porcine therapies,
including extracorporeal liver perfusion (n 1),
extracorporeal kidney perfusion (n 2), bioartificial
liver perfusion (n 28), pancreatic islet transplanta-
116
tion (n 14), skin grafting (n 15), and extracorporeal splenic perfusion (n 100). All therapies used
living porcine cells at the time of human exposure.
Patients ranged in age from 2 to 77 years at the time of
exposure. The duration of exposure to porcine tissue
ranged from 15 minutes (extracorporeal pig kidney
perfusion) to 460 days (porcine pancreatic islet transplantation). The follow-up interval from treatment
ranged from less than 1 day to 12 years (mean, 38
months).
At least one set of blood samples was obtained from
each patient to obtain PBMCs and serum for analysis.
Samples were analyzed in four laboratories using
multiple recently developed assays specific for PERV:
(1) polymerase chain reaction (PCR) for detection of
PERV DNA and pig DNA in PBMCs, (2) RT-PCR for
detection of PERV RNA in serum, and (3) protein
immunoblot analysis for detection of antibodies to
PERV in serum. In some cases, samples of saliva were
also collected for detection of PERV RNA by RT-PCR.
PCR testing showed that the PBMCs of 125
patients (81%) were negative for PERV DNA. This
group included all 29 patients who had undergone
either extracorporeal perfusion with a pig liver or
porcine bioartificial liver. Of the 30 patients found to
contain PERV DNA in their PBMCs, 23 also contained other sequences of pig DNA and were therefore
interpreted as microchimeric. The 23 patients found to
contain microchimerism had undergone extracorporeal splenic perfusion. The status of the remaining
patients was not interpretable because of insufficient
DNA for analysis. These PCR results were supported
by screening assays for PERV antibodies and RT-PCR
testing for PERV RNA. None of the serum and saliva
samples from these 160 patients, along with 5 close
contacts, contained PERV RNA. Four of 160 patients
were seroreactive to PERV Gag proteins, although
none of the 4 patients had other molecular evidence of
PERV infection.
A small number of unexplained symptoms were
noted by patients exposed to porcine tissue. Three
patients reported skin rashes after treatment with the
porcine bioartificial liver. One of these patients also
reported a 4-day febrile episode that was otherwise
unexplained. An ongoing skin rash was noted in a
patient after porcine skin grafting. All PERV testing
was negative in these 4 patients.
A few weaknesses of the study are apparent, primarily because of its retrospective nature. For example,
four separate laboratory sites were involved in sample
analysis. As a result, similar tests were conducted with
different primers, antigens, and methods. To provide a
117
References
1. Paradis K, Langjord G, Long Z, Heneine W, Sandstrom P,
Switzer W, et al. Search for cross-species transmission of porcine
endogenous retrovirus in patients treated with living pig tissue.
Science 1999;285:1236-1241.
2. Abouna GM, Garry R, Hull C, Kirkley J, Walder DN. Pig-liver
perfusion 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 time has come. Am J
Gastroenterol 1993;88:1876-1881.
4. Chari RS, Collins BH, Magee JC, DiMaio JM, Kirk AD,
Harland RC, et al. Treatment of hepatic failure with ex vivo
pig-liver perfusion followed by liver transplantation. N Engl J
Med 1994;331:234-236.
5. Makowa L, Cramer D, Hoffman A, Breda M, Sher L, EirasHreha G, et al. The use of a pig liver xenograft for temporary
support of a patient with fulminant hepatic failure. Transplantation 1995;49:1654-1659.
6. Watanabe F, Mullon CJ-P, Hewitt W, Arkadopoulos N, Kahaku
E, Eguchi S, et al. Clinical experience with a bioartifical liver
(BAL) in the treatment of severe liver failure: A phase I clinical
trial. Ann Surg 1997;225:484-494.
7. Patience C, Takeuchi Y, Weiss R. Infection of human cells by an
endogenous retrovirus of pigs. Nat Med 1997;3:282-286.
8. Martin U, Kiessig V, Blusch J, Haverich A, von der Helm K,
Herden T, et al. Expression of pig endogenous retrovirus by
primary porcine endothelial cells and infection of human cells.
Lancet 1998;352:692-694.
9. Wilson C, Wong S, Muller J, Davidson C, Rose T, Burd P. Type
C retrovirus released from porcine primary peripheral-blood
mononuclear cells infects human cells. J Virol 1998;72:30823087.
10. Armstrong J, Porterfield J, De Madrid A. C-type virus particles
in pig kidney cell lines. J Gen Virol 1971;10:195-198.
11. Todaro G, Benveniste R, Lieber M, Sherr C. Characterization of
a type 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 and
immunologic properties of porcine type C viruses. Virology
1975;66:616-619.
13. Takeuchi Y, Patience C, Magre S, Weiss R, Banerjee P, LeTissier
P, et al. Host range and interference studies on three classes of
pig endogenous retrovirus. J Virol 1998;72:9986-9991.
14. Le Tissier C, Staye J, Takeuchi Y, Patience O, Weiss R. Two sets
of human-tropic pig retrovirus. Nature 1997;389:681-682.
15. Nyberg S, Hibbs J, Hardin J, Germer J, Platt J, Paya C, et al.
Influence of human fulminant hepatic failure sera on endogenous retroviral expression in pig hepatocytes. Liver Transpl
2000;6:76-84.
16. Stoye J. No clear answers on safety of pigs as tissue donor source.
Lancet 1998;352:666-667.
17. Weiss R. Xenografts and retroviruses. Science 1999;285:12211222.
18. Patience C, Patton G, Takeuchi Y, Weiss R, McClure M,
Rydberg L, et al. No evidence of pig DNA or retroviral infection
in 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
Comments
In the practice of transplantation, most clinicians and
surgeons have had the unfortunate and disconcerting
experience of having a patient develop a malignancy
posttransplantation, with rapid progression of the
disease. One clinical question emanating from these
observations is always whether immunosuppressive
drugs themselves directly affect cell transformation.
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These issues are especially germane to liver transplantation because this procedure is often performed on
people with malignant diseases. If specific immunosuppressive agents directly alter tumor biological characteristics, they likely will also impact on outcome after liver
transplantation for malignant diseases. This information is important for selecting the best immunosuppressive regiment for these specific patient populations.
The report by Hojo et al1 attempts to answer the
question, does cyclosporine directly affect tumor biology? First, they directly evaluated the effect of cyclosporine on the malignant phenotype in vitro by using a
nontransformed human pulmonary adenocarcinoma
(A-549) cell line. Cells cultured in the presence of
cyclosporine (1 g/mL) showed anchorage-independent proliferation (an assay correlating with invasive
tumor growth) and enhanced cell motility (an assay for
metastases). Second, experiments were performed to
determine the effect of cyclosporine on the metastatic
potential of a cancer in vivo. Murine renal adenocarcinoma cells showed increased metastases in immunodeficient (SCID) mice treated with cyclosporine (20
mg/kg orally every other day). The effects were associated with the ability of cyclosporine to increase
transforming growth factor- (TGF-) secretion by
the tumor cells and were blocked by monoclonal
antibodies to TGF-. The data were interpreted to
suggest that cyclosporine can promote cancer progression by direct effects on tumor cells independent of
their potential inhibition of immune surveillance. This
provocative study, published in a high-impact journal,
raises several key questions germane to the practice of
liver transplantation. These issues are discussed in the
following paragraphs.
Do the results of this study pertain to other
calcineurin inhibitors? The answer to this question is
likely. Tacrolimus, the other calcineurin inhibitor used
clinically, also increases TGF- generation at clinically
used concentrations.2 If the enhancement of the malignant phenotype is TGF- mediated, then either cyclosporine or tacrolimus should cause similar phenotypic
alterations.
Can these data be extrapolated to transplant populations? The answer to this question is difficult to
address. First, the concentration dependence of the
data was not provided, and the concentrations of
cyclosporine used in these studies are greater than those
used in clinical transplantation. Second, TGF- does
not promote invasive behavior in all malignancies. For
example, TGF- induces cell-cycle arrest and apoptosis
in many hepatocellular carcinoma (HCC) cell lines.3
TGF- has even been suggested to be a tumor-
suppressor ligand.4 Despite these observations, cyclosporine has been shown to enhance the growth of
HCC cells and promote early recurrence in an animal
model of transplantation for HCC, perhaps by an
effect independent of TGF-.5 These observations
make it likely that cyclosporine directly enhances the
malignant phenotype in many solid tumors, including
HCCs.
Should this basic study impact on how we practice?
The answer is perhaps. First, this study should not alter
the way patients are counseled regarding the risks of
immunosuppression. Only skin cancer, lymphoma,
cervical cancer, and Kaposis sarcoma appear to be
increased in liver transplant recipients.6 These cancers,
aside from skin cancers, are related to viruses, and their
oncogenesis is uniquely different from other solidtissue malignancies. The most common solid-organ
tumors occurring in humans, breast, lung, and colon
cancers, are not increased in this patient population,
aside from patients with ulcerative colitis who undergo
transplantation for primary sclerosing cholangitis. These
patients are known to be at high risk for colon cancer
with or without transplantation. In this respect, it is
important to note that cyclosporine was not suggested
to promote tumor development in the study by Hojo
et al,1 but only the invasiveness of established cancers.
However, this study may alter our choice of immunosuppressants when liver transplantation is performed
for malignant disease.
The importance of this issue is highlighted by the
recent availability of rapamycin as an immunosuppressive agent. Rapamycin is growth inhibitory for transformed cell lines and has recently been used successfully as monotherapy in liver transplant recipients.7
Pilot studies comparing a classic calcineurin inhibitor
versus rapamycin after transplantation for malignant
disease are needed to answer this question in the era of
evidence-based medicine. However, it is possible that
rapamycin will become the agent of choice for these
patients in the future, based on studies like the one by
Hojo et al.1
In summary, I believe this study is a clinical mirror
to the future and not an experimental mirage. We are
now approaching the era of selected immunosuppression for different patient populations.
Gregory J. Gores, MD
Professor of Medicine
Mayo Clinic
200 First Street, SW
Rochester, MN 55905
119
References
1. Hojo M, Morimoto T, Maluccio M, Asano T, Morimoto K,
Lagman M, et al. Cyclosporine induces cancer progression by a
cell-autonomous mechanism. Nature 1999;397:530-534.
2. Khanna A, Cairns V, Hosenpud JD. Tacrolimus induces increased
expression of transforming growth factor-beta1 in mammalian
lymphoid as well as nonlymphoid cells. Transplantation 1999;67:
614-619.
3. Gressner AM, Lahme B, Mannherz HG, Polzar B. TGF-beta
mediated hepatocellular apoptosis by rat and human hepatoma
cells and primary rat hepatocytes. J Hepatol 1997;26:1079-1092.
4. Tang B, Bottinger EP, Jakowlew SB, Bagnall KM, Mariano J,
Anver MR, et al. Transforming growth factor-beta1 is a new form
of 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 cyclosporine on tumor recurrence after liver transplantation in a model of hepatocellular carcinoma. Transplantation
1999;67:510-513.
6. Penn I. Posttransplantation de novo tumors in liver allograft
recipients. Liver Transpl Surg 1996;2:52-59.
7. Watson CJ, Friend PJ, Jamieson NV, Frick TW, Alexander G,
Gimson AE, et al. Sirolimus: A potent new immunosuppressant
for liver transplantation. Transplantation 1999;67:505-509.
Comments
Liver transplantation remains one of the most expensive surgical procedures performed today.1,2 As a result,
third-party payers, providers, and public policymakers
have an acute interest in containing, if not reducing,
costs. Expense management is hardly a minor issue; it
is a major concern.
To address these issues, managed care organizations
have resorted to centers of excellence contracting and
case management.3-7 Based on the available evidence,
their efforts have apparently been successful. In 1993,
the actuarial firm, Milliman & Robertson, estimated
that the total first-year charges associated with liver
transplantation were $302,900.8 By 1996, this figure
increased to $314,500.9 However, in their most recent
report, Milliman & Robertson indicated that the total
first-year charges for liver transplantation have decreased significantly to $244,600.10
Unfortunately, most studies concerning the cost of
liver transplantation have actually focused on nonstandardized billed charges, which often bear little relationship to actual accounting costs. This issue has been
addressed at length in the literature.11,12
In an exceptional effort to overcome many of the
problems associated with previous analyses of liver
transplantation costs, Showstack et al,13 in a threecenter analysis, used a standard price list to value
resource utilization. Although their analysis excluded
all professional fees, they were able to examine in
exquisite detail the initial transplantation hospitalization for 711 patients who were aged 16 years or older,
had nonfulminant liver disease, and for whom the liver
was the only organ transplanted. Multivariate models
were tested in an effort to assess the independent
associations of resource utilization with patient demographic and clinical characteristics.
120
Financial
Indicator
Gross charges ($)
Adjusted charges
($)
Reimbursement
($)
Cost ($)
Margin ($)
Margin as a percentage of cost
(%)
Gross deductions
from revenue
(%)
Moderate
Low
32,091
16,686
8269
14,208
9461
3903
7709
5133
2576
6683
5077
1606
3151
2480
671
50
32
27
46
29
19
*Definition of managed care penetration: high, 59%; moderate, 35%; low, 11%.
Case-mix and wage-index adjusted.
References
1. Evans RW. Organ transplantation and the inevitable debate as to
what constitutes a basic health care benefit. In: Terasaki P, Cecka
M (eds). Clinical transplants 1993. Los Angeles: UCLA Tissue
Typing Laboratory, 1994:359-391.
2. Evans RW. Effect of liver transplantation on local, regional, and
national health care. In: Busuttil RW, Klintmalm GB (eds).
Transplantation of the liver. Philadelphia: Saunders, 1996:869879.
3. Ascher NL, Evans RW. Designation of liver transplant centers in
the United States. Transplant Proc 1987;19:2405.
4. Evans RW. Public and private insurer designation of transplantation programs. Transplantation 1992;53:1041-1046.
5. Dahlberg R. Centers of excellence. Managed Care Q 1997;5(3):
86-88.
6. Albrecht GL, Fitzpatrick R (eds). Advances in medical sociology.
Case and care management. Stanford: JAI Press, 1995.
7. Mayer GG. Case management as a mind set. Qual Manage
Health Care 1996;5(1):7-16.
8. Hauboldt RH. Cost implications of human organ transplantations, an update: 1993. Brookfield: Milliman & Robertson,
1993.
9. Hauboldt RH. Cost implications of human organ and tissue
transplantations, an update: 1996. Brookfield: Milliman &
Robertson, 1996.
121