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Transplantation: Volume 63(10) 27 May 1997 pp 1521-1524

ORTHOTOPIC LIVER TRANSPLANTATION FOR VENO-

OCCLUSIVE DISEASE COMPLICATING AUTOLOGOUS BONE
MARROW TRANSPLANTATION
Norris, Suzanne1,2; Crosbie, Orla1; McEntee, Gerry1; Traynor, Oscar1; Nolan, Niamh3; McCann, Sean4;
Hegarty, John1
Liver Unit and Department of Histopathology, St. Vincent's Hospital, Dublin 4, and Department of Haematology, St.
James's Hospital, Dublin 8, Ireland
1
Liver Unit, St. Vincent's Hospital.
2
Address correspondence to: Suzanne Norris, Liver Unit, St. Vincent's Hospital, Elm Park, Dublin 4, Ireland.
3
Department of Histopathology, St. Vincent's Hospital. Article Outline
4
Department of Haematology, St. James's Hospital.
 Abstract
Received 28 August 1996.
Accepted 21 January 1997.  Footnotes [Context Link]
 REFERENCES
Abstract TOP Figures/Tables
Background . Veno-occlusive disease of the liver is a serious  Figure 1
and often life-threatening complication after bone marrow
transplantation. Although risk factors for the development of
veno-occlusive disease have been postulated, there is no  Figure 2
precise method for accurately identifying those patients who are at risk and for whom early intervention and
treatment would have maximum potential benefit. Liver transplantation has been advocated as a treatment
for veno-occlusive disease in selected patients.
Methods . In this report, we describe a patient who underwent liver transplantation for life-threatening veno-
occlusive disease after autologous bone marrow transplantation for acute lymphoblastic leukemia.
Results . Liver engraftment was achieved, but the patient developed Pneumocystis pneumonia, which failed
to respond to pentamidine. The patient died 6 months after liver transplantation.
Conclusions . While acknowledging the limited experience of orthotropic liver transplantation in this patient
population, we suggest its consideration as a feasible, potentially beneficial treatment option in patients
with severe veno-occlusive disease after bone marrow transplantation.
In the absence of a compatible sibling donor, autologous bone marrow transplantation (ABMT*) is a
recognized modality of therapy for patients with hematological malignancies. ABMT can be associated with
significant morbidity and mortality arising on a background of post-BMT complications, which include graft-
versus-host disease, veno-occlusive disease (VOD), and sepsis (1). VOD occurs in 10% and 20% of ABMTs
and allogeneic BMTs, respectively (2-4), and in a reported series has a documented mortality of 20-50% from
fulminant hepatic failure and other associated complications (2, 4). Medical therapies for severe VOD-related
liver failure have largely been unsuccessful, and consideration has been given to liver transplantation in these
patients (5-7). We herein report the successful treatment of hepatic failure secondary to VOD complicating
ABMT for acute lymphoblastic leukemia with orthotopic liver transplantation.
A 25-year-old male presented in August 1993 with a 1 wk history of anorexia, weight loss, abdominal pain, and
purpura over the trunk and lower extremities. Investigations revealed white cell count of 34.9×10 9/L (70%
lymphocytes, 15% neutrophils), hemoglobin of 13.6 g/dL, and platelets of 10×10 9/L. Biochemical renal and
liver function were normal. Bone marrow aspirate and bone biopsy were consistent with acute lymphoblastic
leukemia of the T-cell type (71% blasts). Complete remission was achieved after induction therapy with
prednisolone, vincristine, daunorubicin, and L-asparaginase. ABMT with 1.7×10 9 nucleated cells/kg was
performed in February 1994, after conditioning treatment with busulfan at 16 mg/kg for 4 days and
cyclophosphamide at 120 mg/kg for 2 days. Granulocyte colony-stimulating factor was started on day 1 after
BMT. Engraftment occurred and isolation was broken 11 days later.
Three weeks after BMT, the patient complained of abdominal pain, and examination revealed right upper
quadrant tenderness and ascites. Liver function tests (LFTs) revealed bilirubin of 40 μmol/L, aspartate
aminotransferase (AST) of 80 U/L, and the remaining profile was normal; the international normalized ratio
(INR) was 1.2. The patient's clinical condition deteriorated over the next 10 days with progressive jaundice,
increasing ascites, peripheral edema, a significant weight gain of 24 kg by day 30, and thrombocytopenia
(platelets 13×109/L), which proved to be refractory to platelet transfusions. Biochemical parameters continued
to deteriorate with bilirubin rising to 352 μmol/L and AST to 942 U/L, with concurrent development of a
coagulopathy (INR 2, platelets 7). Renal function remained normal. Abdominal CT scan confirmed gross
ascites and hepatomegaly, whereas duplex ultrasound scan revealed clearly patent hepatic veins and inferior
vena cava with normal blood-flow patterns. Angiography was not performed, in view of deteriorating status
with coagulopathy and refractory thrombocytopenia.
Based on a presumptive diagnosis of VOD, thrombolysis was commenced with tissue plasminogen activator at
10 mg/kg and heparin at 100 IU/kg/day. Despite this treatment, the patient's condition continued to deteriorate,
with INR rising to 2.5 and the onset of hepatic encephalopathy necessitating referral on day 31 for assessment
for liver transplantation. Within 12 hr, an ABO-incompatible (donor O +, recipient B+) cytomegalovirus-positive
donor organ became available and orthotopic liver transplantation was performed on day 32 after BMT.
Hepatectomy was particularly difficult due to the enormous size of the native liver, which weighed 2950 g.
Microscopic examination of the explanted organ, which was enlarged and congested, revealed marked
congestion in the perivenular zones with thinning of liver cell plates and hepatocyte cell loss in those regions
(Fig. 1). The large hepatic veins showed no evidence of intraluminal thrombosis. The terminal hepatic venules
showed variable degrees of narrowing by edematous fibrillar material (Fig. 2), which did not contain
elastin, mature collagen, or fibrin (negative Elastic Van Gieson, Orcein, and MSB
stains). These findings were compatible with nonthrombotic occlusive disease.

Figure 1. Terminal hepatic venules and perivenular zone showing intense congestion, atrophied liver cell plates, and loss of
hepatocytes in the immediate perivenular region. Hematoxylin and eosin, ×40.

Figure 2. Terminal hepatic venule totally occluded by fibrillar material. Reticulin, ×40
Post-operative immunosuppression consisted of cyclosporine at 1 mg/kg every 12 hr and methylprednisolone
at 50 mg/day, with prophylactic ganciclovir (5 mg/kg intravenously) for 14 days. Complications after liver
transplant included transient impairment of renal function (creatinine of 205 μmol/L; urea of 25 mmol/L)
requiring continuous venovenous hemodialysis for 48 hr, and left basal pneumonia, which responded to
appropriate antimicrobial agents. An unsupported platelet count of >20×10 9/L was achieved by day 6 after OLT
and bone marrow aspirate performed on day 7 confirmed normal hematopoiesis and megakaryocyte numbers
with no evidence of leukemia. The INR had returned to normal by day 9 after OLT. The white cell count
remained above 4×109/L. After discharge, at a clinic review at 4 wk after OLT, LFTs had deteriorated with
serum bilirubin levels of 163 μmol/L, alkaline phosphatase of 472 U/L, γ-glutamyl-tranferase of 523 U/L,
alanine aminotransferase of 1075 U/L, and AST of 452 U/L. Liver biopsy confirmed a mixed inflammatory
infiltrate in the portal tracts with endothelitis, marked bile duct damage, central perivenular ballooning, and
cholestasis compatible with acute cellular rejection. Two cycles of high-dose steroids (methylprednisolone 1 g
daily for 3 days) were required before improvement in liver function was obtained. Unfortunately, over
successive months, LFTs deteriorated with liver biopsy revealing features of chronic rejection. Rescue therapy
with tacrolimus (FK506) was commenced and three consecutive weekly trough levels of 10-20 mg/L were
achieved. However, further deterioration in clinical status occurred with the development of Pneumocystis
pneumonia, which failed to respond to pentamidine. The patient died 6 months after liver transplant. There
was no evidence of cytomegalovirus infection or post-transplant lymphoproliferative disease during the
postoperative course or at time of death.
VOD is the third leading cause of morbidity and mortality after BMT, with mortality approaching 50% from
fulminant hepatic failure and its associated complications (2, 4). Several risk factors predisposing to the
development of VOD have been identified and include the relationship with preexisting liver disease and high-
dose chemotherapy, in particular busulfan (8, 9). In addition, the use of vancomycin and acyclovir before BMT
have been identified as independent risk factors for VOD (10). Further studies have shown that persistent
elevation in alkaline phosphatase and AST before BMT is significantly associated with increased risk of VOD,
whereas age, sex, type of graft, diagnosis, preparative regimen, and hepatitis B antigen are not consistently
associated with an increased risk of this complication (4). Adverse prognostic features with respect to outcome
have been identified, with some studies indicating that the peak bilirubin level and the development of hepatic
encephalopathy are highly significant with respect to outcome (4). Hepatic venous pressure gradient was also
found to be a determinant of outcome, as suggested by one study in which all patients who developed VOD
and had a hepatic venous pressure gradient >13 mmHg died (11). Bearman also reports the percentage of
weight gain as a significant prognostic factor (12).
The frequent occurrence of VOD after BMT has led to the evaluation of the prophylactic use of thrombolytic
and antifibrinolytic therapies with conflicting results. Low-dose heparin has been associated with a reduction in
incidence of VOD (13), but this has not been confirmed by subsequent work (14). Reports of the prophylactic
use of prostaglandin E1 have also yielded conflicting results (15, 16). In one nonrandomized trial, by
modulating tumor necrosis factor-α production and stimulating vascular endothelial production of non-
inflammatory prostaglandins, pentoxifylline was associated with reduced incidence of VOD and graft-versus-
host disease (17). More specific approaches for re-establishing venular flow have been used, including
thrombolytic agents such as recombinant tissue plasminogen activator and heparin administered over a 4-day
period (18). With this regimen, improvement in both clinical and biochemical parameters has been reported;
however, the regimen did not reverse the clinical course for our patient.
Orthotopic liver transplantation has been successfully performed in two reported cases (5, 6) in which VOD
developed after allogeneic BMT. Living-related liver transplantation has been described as a treatment for
VOD after a T cell-depleted unrelated donor BMT in a third case (7). Ideally, liver transplantation for VOD after
BMT should be reserved for those patients who exhibit prognostic indicators indicative of fatal outcome, but for
whom such indicators are not clearly defined. One study of 53 patients who developed VOD after BMT
retrospectively analyzed those patients who died of VOD-related hepatic complications (serious VOD) and
compared them with those who recovered (nonserious VOD). The study reported a significantly higher bilirubin
(P<0.0001) and AST (P=0.02) in those with serious VOD (3). The patients in this group also exhibited a higher
maximum weight gain (P=0.02), and a higher percentage developed encephalopathy (69% vs. 29%
nonserious VOD). It is therefore reasonable to advocate OLT for VOD-related hepatic failure after BMT in the
presence of rapidly deteriorating LFTs, particularly AST and bilirubin, rapid onset of ascites, and
encephalopathy. Mesocaval shunt surgery was considered in this case, but was deemed inappropriate.
Although patients with potentially reversible hepatic injury and with stable liver function can be managed
successfully by a decompressive shunt, a fulminant course (as demonstrated by our patient) necessitates
transplantation. Although the histology of the explanted liver showed no evidence of chronic liver disease, the
clinical and biochemical characteristics of our patient (high serum bilirubin, encephalopathy, significant weight
gain) indicated a low probability of recovery and poor outcome.
This report, together with the other three cases, obviously represents a very limited experience in treating
serious VOD after BMT. Our patient died at 6 months after liver transplantation from overwhelming
opportunistic infection with Pneumocystis carinii. Although repeated high-dose steroids used to treat acute
rejection may have contributed to the development of this complication, it is a relatively common sequela of
BMT alone. Our patient had a documented allergy to trimethoprim/sulfamethoxazole (Septrim, Burroughs
Wellcome, Research Triangle Park, NC), which prevented its prophylactic use after liver transplant. This may
have been a contributory factor to the subsequent development of Pneumocystis pneumonia. In the absence
of this complication, retransplantation for chronic rejection would have been advocated. Chronic rejection
occurs in less than 10% of transplant recipients and factors implicated have included multiple or poorly
controlled acute rejection episodes. Although ABO incompatibility has not similarly been clearly implicated, it is
associated with poorer outcome as a result of higher frequency of severe rejection, vascular thrombosis, and
bile duct complications, and may have contributed to the development of chronic rejection in this case. In
trials, tacrolimus has been associated with a lower incidence of acute, acute refractory, and chronic rejection
compared with cyclosporine (19), and therefore may be the preferred primary immunosuppressive agent in the
setting of ABO-incompatible donors.
We believe this to be the first reported case of VOD after ABMT. While acknowledging the limited experience
of OLT in this patient population, we suggest its consideration as a feasible, potentially beneficial treatment
option in patients with severe VOD after BMT. Further reports with longer follow-up data will allow precise
definition of the role of liver transplantation in treating VOD.
Footnotes [Context Link] TOP
REFERENCES TOP
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© Williams & Wilkins 1997. All Rights Reserved.
Citing Articles TOP
Life-threatening veno-occlusive disease after living-related liver
transplantation.
Transplantation. 75(5):727-730, March 15, 2003.
Nakazawa, Yuichi 1; Chisuwa, Hisanao 1; Mita, Atsuyoshi 1; Ikegami, Toshihiko 1;
Hashikura, Yasuhiko 1; Terada, Masaru 1; Nakayama, Jun 2; Kawasaki, Seiji 1
[Abstract] [Fulltext] [PDF (1.05 M)]

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