Download Hepatic Veno-occlusive Disease (Sinusoidal Obstruction Syndrome

Mayo Clin Proc, May 2003, Vol 78
Hepatic Veno-occlusive Disease
589
Review
Hepatic Veno-occlusive Disease (Sinusoidal Obstruction Syndrome)
After Hematopoietic Stem Cell Transplantation
SHAJI KUMAR, MD; LAURIE D. DELEVE, MD; PATRICK S. KAMATH, MD; AND AYALEW TEFFERI, MD
mon conditions can mimic it. Limited therapeutic or preventive strategies are currently available for the management of VOD. In this review, we provide a comprehensive
account of the pathophysiology of this disease as we understand it today, risk factors for its development, and the
current state of knowledge regarding preventive and
therapeutic options.
Mayo Clin Proc. 2003;78:589-598
Hepatic veno-occlusive disease (VOD), increasingly referred to as sinusoidal obstruction syndrome, is a wellrecognized complication of hematopoietic stem cell transplantation and contributes to considerable morbidity and
mortality. In the Western Hemisphere, VOD, classified as
a conditioning-related toxicity, is most commonly caused
by stem cell transplantation. VOD has been described after all types of stem cell transplantation, irrespective of the
stem cell source, type of conditioning therapy, or underlying disease. Recognition of this disease in the posttransplantation setting remains a challenge in the absence of
specific diagnostic features because many other more com-
PAI = plasminogen activator inhibitor; PG = prostaglandin;
TBI = total body irradiation; tPA = tissue-type plasminogen
activator; VOD = veno-occlusive disease
H
epatic veno-occlusive disease (VOD) as a distinct
clinical entity was first described in South Africa and
was linked to the ingestion of pyrrolizidine alkaloids contained in Senecio tea.1 The characteristic occlusion of the
terminal venules of the liver in the individuals who drank
this tea led to the term veno-occlusive disease. On the basis
of more recent work suggesting that the sinusoidal changes
are primary events in the pathology of the disease, the term
sinusoidal obstruction syndrome may describe the condition better.2 Several species of plants containing pyrrolizidine alkaloid can cause VOD and have been associated
with epidemics of this disease in underdeveloped nations.3,4
VOD developing after allogeneic stem cell transplantation
was first described in 1979,5,6 and stem cell transplantation
has since become the most common cause of VOD in the
Western Hemisphere.7-9 However, VOD also has been described in association with chemotherapeutic agents such
as actinomycin D,10 mithramycin, dacarbazine,11 cytosine
arabinoside, and 6-thioguanine12 used at conventional
doses and with long-term use of the immunosuppressive
agent azathioprine.13 More recently, VOD has been seen
after therapy for acute myelogenous leukemia with the
monoclonal anti-CD33 antibody gemtuzumab ozogamicin
(Mylotarg).14 The combination of chemotherapy and radiation used in abdominal areas, for example in children with
Wilms tumor, has been associated with development of
VOD.15 Also, VOD is seen after liver transplantation.16
VOD is a well-recognized complication of hematopoietic stem cell transplantation, both allogeneic and autologous, and is categorized as a conditioning-related toxicity.7-9,17 The incidence of this condition varies from less
than 5% to as high as 70% in different reports, depending
on the diagnostic criteria used, the population studied (eg,
pediatric vs adult), and the differences in conditioning
therapy used.7,18-20 Because VOD contributes to considerable morbidity and mortality among patients undergoing
stem cell transplantation, gaining an understanding of its
pathogenesis and developing new modalities for its prevention and therapy remain important tasks.
PATHOLOGY
The characteristic histological changes seen in VOD have
been studied extensively and are best understood in the
setting of normal liver histology.8,21,22 Hepatocytes have a
canalicular surface, which forms the bile canaliculi, and a
basolateral sinusoidal surface. The sinusoidal surface is
lined by a single layer of endothelial cells, the fenestrae of
which allow free communication between the sinusoids
and the extravascular space of Disse. A delicate network of
collagen fibers supports the sinusoidal lining, and there is a
scant amount of subendothelial stromal tissue. The hepatic
parenchyma is organized classically into lobules based primarily on the vascular architecture. Each lobule is arranged
From the Division of Hematology and Internal Medicine (S.K., A.T.)
and Division of Gastroenterology and Hepatology and Internal Medicine (P.S.K.), Mayo Clinic, Rochester, Minn; and USC Research
Center for Liver Diseases and Division of Gastrointestinal and Liver
Diseases, University of Southern California Keck School of Medicine, Los Angeles (L.D.D.).
Address reprint requests and correspondence to Ayalew Tefferi, MD,
Division of Hematology, Mayo Clinic, 200 First St SW, Rochester,
MN 55905 (e-mail: [email protected]).
Mayo Clin Proc. 2003;78:589-598
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© 2003 Mayo Foundation for Medical Education and Research
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Hepatic Veno-occlusive Disease
around a hepatic venule, and the portal triad containing the
bile ductule, portal venule, and hepatic arterioles forms the
corners of the hexagonal lobule, defining a functional and
circulatory compartment of the liver. The zone around the
portal triad has a rich vascular supply from the portal
venous system and defines the periportal zone. The central
region of the lobule close to the hepatic venules forms the
centrilobular zone. The sinusoids form the venous conduits
for the flow from the portal vein to the hepatic venules.
Endothelial injury seems to be the initiating event in the
cascade of events leading to the hepatic changes and clinical manifestation of VOD. A rat model of hepatic VOD has
been described that has contributed much to our understanding of events that lead to the development of the
histological changes.23 In this model, the hepatic injury is
initiated by treatment with a pyrrolizidine alkaloid extracted from the plant genus Crotalaria and leads to manifestations similar to those seen clinically, including hyperbilirubinemia, ascites, and hepatomegaly. In this model,
the earliest changes after alkaloid ingestion appear in the
sinusoids. This leads to the loss of the endothelial cell
fenestrations and the appearance of gaps in the lining,
which is followed by extravasation of red cells into the
space of Disse. Sinusoidal endothelial cells are injured
extensively, resulting in widespread denudation of the sinusoidal lining.
In the early stages of VOD, histological examination
findings show thickening of the subintimal zone of the
central and sublobular venules due to edema. Immunohistochemical studies have shown the presence of fibrin and
factor VIII in the intramural and periadventitial portions of
the venular walls.22 Also present in the subendothelial region are red blood cell fragments, but no platelet fragments
have been shown. No inflammatory infiltrate is identified
in the tissue sections. The subintimal thickening leads to
narrowing of the venular lumen and increased resistance to
blood flow through the venules and contributes to the hemodynamic changes seen in this disease. The decreased
venous outflow leads to severe hepatic congestion and
sinusoidal dilatation, appreciated on the histological examination, and portal hypertension characteristic of VOD.
Accompanying these changes in the vascular bed is evidence of hepatocyte injury and death, and these changes
appear to be primarily localized to the centrilobular region
of the liver. The low-flow state induced by the sinusoidal
obstruction results in considerable heterogeneity in sinusoidal blood flow and redistribution of hepatic microcirculation.24,25 These changes can result in focal ischemia and
progressive microvascular, parenchymal, and Kupffer cell
phagocytic derangements in the liver. Mediators such as
5-hydroxytryptamine (5-HT), prostaglandins (PGs), leukotrienes, and free radicals released by platelets, Kupffer
Mayo Clin Proc, May 2003, Vol 78
cells, leukocytes, and mast cells may play a role in the
endothelial damage and the downstream events leading to
hepatocellular ischemia and injury. Shulman et al21 correlated the histological findings in VOD, including frequency
of hepatic venular occlusion, degree of occlusion, eccentric
luminal narrowing, centrilobular sinusoidal fibrosis, and
hepatocyte necrosis. This study showed that involvement
of the hepatic venules was not an essential feature of the
disease, consistent with the concept that the primary obstruction occurs in the sin-usoids, and that more severe
disease was observed in patients who had fibrosis of both
the sinusoids and the venules.
The role of the coagulation pathways in the pathophysiology of VOD is an area of controversy. Although VOD
often is considered a nonthrombotic vascular disease of the
liver, enough evidence exists to consider the contribution
of the hemostatic system in some form.26-29 The most compelling data come from reports of effective treatment of
VOD with use of thrombolytic agents and from reports of
some benefit from prophylactic heparin in the prevention
of VOD. Studies have shown that levels of anticoagulant
proteins such as protein C,27,28 protein S, and antithrombin26,30 are decreased considerably more in patients with
VOD compared with those without VOD. Whether these
changes are secondary to the disease process itself or
whether they lead to thrombotic occlusion of sinusoids is
unclear. Changes in these proteins also have been seen after
the conditioning regimen and before any clinical evidence
of VOD. Levels of procoagulant proteins such as factor
VIII and von Willebrand factor28,31 have been found to be
higher among patients with VOD; however, these could be
related to endothelial injury. Several other markers of
endothelial injury, including thrombomodulin32 and P
selectin33 levels, are elevated in these patients, as are levels
of markers that indicate activation of the coagulation system, such as thrombin-antithrombin complexes and prothrombin fragment 1+2.28,30 Despite the substantial changes
that indicate activation of the coagulation system, actual
thrombi seen within the venules or sinusoids is uncommon.21 It is likely that the cellular debris from the sloughing
of the endothelium, the subintimal thickening, and the
fixed obstruction by sinusoidal and venular fibrosis play a
more important role in the vascular obstruction than thrombosis. Levels of multiple cytokines, such as tumor necrosis
factor α, interleukin 1, interleukin 2, and transforming
growth factor β,34,35 have been shown to be elevated in
patients before development of VOD and hence may be
involved in its pathogenesis. Many of these cytokines are
released as a response to tissue damage associated with
conditioning. It is also possible that the graft-vs-host reaction contributes to the endothelial damage because the
prevalence of VOD is higher in unrelated and mismatched
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transplant recipients and lower in syngeneic7 and T-cell–
depleted transplant recipients.36
The later stages of VOD are characterized by a strong
fibrotic reaction in the sinusoids; that reaction in the central
venules leads to obliteration of the venules.21 Fibrosis demonstrated in this setting with special stains can help in
making the diagnosis. These changes can lead to signs of
chronic venous outflow obstruction. The presence of activated stellate cells has been shown in the sinusoidal region
in patients with VOD; these cells may be responsible for
the development of fibrosis in VOD.37 Elevated levels of
transforming growth factor β seen in these patients
posttransplantation also may play a role in the development
of fibrosis.
RISK FACTORS
Various patient characteristics pertaining to the pretransplantation and transplantation phases have been implicated
in the pathogenesis of VOD (Table 114,17,38-48). VOD has
been seen in patients undergoing transplantation irrespective of the type (allogeneic vs autologous), source of
stem cells (peripheral blood vs bone marrow), donor type
(matched vs haploidentical vs unrelated), and the type of
conditioning (conventional vs nonmyeloablative transplantation). It is widely believed that the incidence of VOD is
higher in patients who undergo allogeneic stem cell transplantation compared with those who undergo autologous
stem cell transplantation; however, some studies have failed
to substantiate this belief.7,17 A large study from the European Transplant Registry19 showed a significantly higher
incidence of VOD in allogeneic transplant recipients.
The differences observed between patients who undergo
autologous vs allogeneic transplantation may be more a
function of the differences in conditioning regimens. The
reported incidence varies between different series depending on the diagnostic criteria used. VOD tends to be more
severe in patients who undergo allogeneic transplantation,
likely a reflection of the intensity of conditioning regimens,
thus explaining the relatively higher incidence seen in studies using less sensitive diagnostic criteria. The conditioning
regimen is considered one of the important factors in the
pathogenesis of VOD; cyclophosphamide, busulfan, and/or
total body irradiation (TBI) are most commonly associated
with onset of VOD.17 In vitro and animal experiments have
shed light on the possible mechanism of hepatic damage
due to cyclophosphamide.49 Cyclophosphamide is metabolized by cytochrome P-450 in hepatocytes and is converted
into acrolein and phosphoramide, the latter being the therapeutically active metabolite. Acrolein generated by hepatocytes damages the adjacent endothelial cells, and this process is inhibited by glutathione.50-53 When large doses of
cyclophosphamide are administered as part of a condition-
Hepatic Veno-occlusive Disease
591
Table 1. Risk Factors for Veno-occlusive Disease
Pretransplantation factors
Preexisting liver dysfunction (elevated transaminases, fibrosis or
cirrhosis, low pseudocholinesterase level or low albumin level
pretransplantation)17
Presence of hepatic metastases38
Advanced age
Prior radiation treatment of the liver17
Use of vancomycin or acyclovir in the pretransplantation period17
Previous stem cell transplantation17
Prior therapy with gemtuzumab ozogamicin (Mylotarg)14
? Viral hepatitis C39-41
? Decreased protein C42
? Factor V Leiden mutation, prothrombin 20210 mutation43,44
Use of norethisterone45
Transplantation-related factors
High-dose conditioning regimens17
Allogeneic transplantation (compared with autologous
transplantation)
Busulfan for conditioning, especially when area under the curve is
>1500 µmol · min–1 · L–1 and combined with cyclophosphamide
Total body irradiation, especially combined with cyclophosphamide46,47
(depends on total dose and fractionation)
Grafts from unrelated donors or related HLA mismatched transplants17
Methotrexate as part of graft-vs-host disease prophylaxis
? Cytomegalovirus infection48
ing regimen, glutathione stores are depleted, leading to
endothelial cell damage by acrolein. This model also explains some of the protection afforded by N-acetylcysteine,
a glutathione precursor administered in some trials. Glutathione has been shown to decrease the incidence of VOD
in animal models.54 Busulfan is another agent that has been
incriminated in VOD, especially when given with cyclophosphamide, the toxicity of which busulfan appears to
enhance. This potentiation is less when cyclophosphamide
is followed by busulfan.55 Oral busulfan has a variable and
unpredictable absorption, and studies have shown a correlation between the area under the curve for busulfan and the
risk of VOD: the risk of VOD increases when the area
under the curve for busulfan is greater than 1500 µmol ·
min–1 · L–1.56,57 In more recent studies, when busulfan is
adjusted to drug levels by close monitoring, a decreased
incidence of VOD has been reported.57 Multiple studies
have shown that the incidence of VOD is higher in transplant recipients who receive TBI, possibly related to repetitive injury to the sinusoidal endothelial cells and to glutathione depletion.46,47 Different fractionated schedules of
TBI have been associated with a lesser risk of VOD.46
Increasing the interval between TBI and cytotoxic therapy
also may decrease the risk of VOD.58
Preexisting hepatic dysfunction as evidenced by elevated transaminases, decreased albumin levels, and/or decreased pseudocholinesterase levels appears to increase
patients’ risk of VOD after transplantation.7,17,19,59 The presence of hepatic metastases especially in the context of solid
tumors,38 prior radiation treatment of the liver,17 and pos-
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Hepatic Veno-occlusive Disease
Table 2. Differential Diagnosis of Veno-occlusive Disease
Acute hepatic graft-vs-host disease
Cyclosporine-induced hepatotoxicity
Fungal infiltration
Viral hepatitis, including cytomegalovirus
Sepsis-related cholestasis (cholangitis lenta)
Drug-induced cholestatic hepatitis (fluconazole, itraconazole,
trimethoprim)
Total parenteral nutrition–related cholestasis
Persistent tumor infiltration into the liver
Congestive heart failure
Neutropenic colitis
sible chronic hepatitis C infection39 all have been reported
to increase the risk of VOD. Other studies have suggested
that the increased risk of VOD with hepatitis C infection
occurs only in the presence of elevated transaminases.40,41
Antibiotic therapy, especially with vancomycin in the immediate pretransplantation period, has been associated
with increased incidence of VOD.17,18 It is unclear whether
vancomycin has any direct effect on VOD or whether it
serves as a surrogate marker for recent infection. Older
patients and those undergoing second transplantations are
definitely at a higher risk of VOD. Some smaller reports
have suggested an increased prevalence of factor V Leiden
mutation43 and prothrombin 20210 mutation44 among those
who develop VOD compared with those who do not. Low
levels of protein C before conditioning therapy may identify patients at a higher risk of VOD.42 Use of methotrexate
as part of graft-vs-host prophylaxis in allogeneic transplant
recipients has been linked to increased risk of VOD compared with use of cyclosporine alone.60 It is unclear whether
acute graft-vs-host disease (GVHD) can contribute to the
pathogenesis of VOD. Patients receiving grafts from unrelated donors and mismatched transplants are at a higher risk
for VOD,17 and there appears to be a decreased risk among
those receiving T-cell–depleted grafts.36 Posttransplantation cytomegalovirus infection may increase the risk of
patients developing VOD.48 Also, use of hormonal agents
such as norethisterone has been associated with increased
risk.45
CLINICAL FEATURES
The clinical features of VOD usually appear toward the end
of the first week or beginning of the second week after
transplantation, and most patients who develop this complication do so within the first 3 weeks after transplantation.61 Some researchers have described late-onset VOD
developing as late as 50 days after transplantation.62 Although these patients have histological features of classic
VOD, it is unclear whether they actually have VOD.
The first sign in most patients is asymptomatic weight
gain, believed to be due to avid retention of water and salt
by the kidneys. This finding is often overlooked in these
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patients because they are receiving various intravenous
preparations, and their weight gain is ascribed to these
infusions. A few days later, isolated hyperbilirubinemia
develops, which is predominantly direct bilirubin, and is
gradually progressive. High levels of bilirubin and a rapid
increase in the direct bilirubin level generally portend severe disease and poor outcome63 and are accompanied or
followed by elevations in alkaline phosphatase and transaminase levels, which often vary in degree of abnormality.
Note that the laboratory finding of especially elevated
alkaline phosphatase levels can be seen in other disorders
such as acute GVHD or fungal infections (Table 2). The
first symptom reported by patients with VOD and often the
only presenting symptom is right upper quadrant pain that
can be severe enough to require narcotic medications.
Physical examination findings in most patients reveal an
enlarged tender liver and the presence of ascites. The ascites and weight gain tend to be refractory to diuretic
therapy in many patients. Evidence of renal dysfunction
manifests in nearly one half of these patients, about 50% of
whom require hemodialysis. A characteristic feature seen
in many of these patients is thrombocytopenia refractory
to platelet transfusions, although clinically severe bleeding
related to thrombocytopenia is uncommon.61,64 This possibly is a result of a combination of increased consumption
due to an ongoing thrombotic process in the sinusoids and
increased splenic sequestration in the presence of splenomegaly related to portal hypertension. Progressive decline
in hepatic function can lead to coagulation factor deficiencies and prolonged prothrombin time. As the disease progresses, some patients may develop severe encephalopathy
and may even become comatose. Many of these patients
develop other conditioning-related toxicities, such as diffuse alveolar hemorrhage and interstitial pneumonitis,65,66
especially in the setting of allogeneic transplantation, again
highlighting the relationship of VOD to the conditioning
regimen and its toxicity.
DIAGNOSIS
A myriad of conditions that affect the liver during the
posttransplantation period can mimic the signs and symptoms of VOD (Table 2), and distinguishing VOD from
these disorders remains a challenge, especially in its early
stages. The gold standard for diagnosis of VOD is the
histological examination of liver tissue. However, because
of the danger of performing a liver biopsy in patients with
thrombocytopenia often refractory to platelet transfusions,
the diagnosis of VOD has been primarily based on clinical
findings. The presence of hyperbilirubinemia, weight gain,
and signs and symptoms of hepatic congestion form the
cornerstone of the diagnosis. The diagnosis of VOD usually is made on the basis of clinical criteria put forth by the
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Seattle7 or Baltimore20 groups (Table 3). In a study comparing Seattle and Baltimore criteria, a diagnosis of VOD
could be confirmed on biopsy in only 42% of patients with
2 features of Seattle criteria compared with 91% of patients
with all 3 features. Baltimore criteria had similar specificity but only 56% sensitivity.67
Ultrasonography usually fails to show any parenchymal
abnormality in VOD. Doppler evidence of portal hypertension, including reversal of portal flow, can help in making
the diagnosis but is usually a late finding.68 Typically, ultrasonography is more useful in excluding other disorders that
can mimic VOD. Other findings on ultrasonography include ascites, hepatomegaly, attenuated hepatic flow, and
hepatic vein dilatation. Magnetic resonance imaging findings of the liver, which may complement ultrasonographic
findings,69 include hepatomegaly, hepatic vein narrowing,
periportal cuffing, gallbladder wall thickening, ascites, and
signs of reduced portal venous flow velocity.
Histological examination of biopsy specimens is the
definitive method of diagnosis. Because of the high risk of
bleeding complications with percutaneous transhepatic biopsy in these patients, a catheter-based percutaneous
transjugular approach is being used increasingly to obtain
liver tissue. This procedure is associated with minimal risk
of bleeding and allows the measurement of wedge hepatic
venous pressures at the same time. Studies have shown that
an elevated hepatic venous pressure gradient can be diagnostic in VOD, especially when it is greater than 10 mm
Hg, and may even have prognostic value.70,71 One disadvantage of the transjugular approach is the small amount of
tissue that can be obtained; however, with modern techniques and equipment, a representative sample adequate
for making the diagnosis can be obtained. Laparoscopic
approaches have been attempted to obtain more tissue. In a
group of 24 patients who underwent laparoscopic biopsies
during the posttransplantation period with platelet transfusion support, no complications occurred, and the procedure
yielded adequate tissue in all patients.72 Advantages of the
laparoscopic approach are the ability to directly visualize
the liver surface and to stop bleeding from the biopsy site
using cautery. However, the histological changes in the
liver of patients with VOD, especially in the early stages,
can be patchy and can lead to false-negative biopsy results.
Elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1) are reportedly a useful marker in distinguishing VOD from other causes of posttransplantation hepatic
dysfunction.73 Available evidence suggests a role for this
molecule in the pathology of VOD. A decrease in the levels
of PAI with use of defibrotide therapy has been seen and
appears to have predictive value for patient response to this
agent.74 Increased uptake of colloidal sulfur by the lungs
has been suggested as a useful predictor of VOD.75 An N-
Hepatic Veno-occlusive Disease
593
Table 3. Diagnostic Criteria for Veno-occlusive Disease
Seattle criteria7
Development of at least 2 of the 3 following clinical features before
day 30 after transplantation
Jaundice
Hepatomegaly with right upper quadrant pain
Ascites and/or unexplained weight gain
Baltimore criteria20
Development of hyperbilirubinemia with serum bilirubin >2 mg/dL
within 21 days after transplantation and at least 2 of the following
clinical signs and symptoms
Hepatomegaly, which may be painful
Weight gain >5% from baseline
Ascites
Modified Seattle criteria18
Development of at least 2 of the 3 following clinical features within
20 days after transplantation
Hyperbilirubinemia with serum bilirubin >2 mg/dL
Hepatomegaly with right upper quadrant pain
Weight gain >2% from baseline body weight due to fluid
accumulation
terminal peptide of type III procollagen has been shown in
a prospective study to be elevated even before conditioning
among patients developing VOD.76
Acute GVHD can involve the liver and result in the
elevation of bilirubin and transaminase levels; when accompanied by right upper quadrant pain, GVHD is difficult
to distinguish from VOD clinically. Although GVHD usually presents later (in the third week onward) in the course
of transplantation compared with VOD, GVHD can present
earlier or VOD can present later in the posttransplantation
period. Weight gain and ascites usually are not a part of
GVHD presentation, and elevation of the alkaline phosphatase level tends to be modest. Other signs such as rash
and diarrhea are often present in GVHD. Confirmation of
the diagnosis of GVHD by skin or other tissue biopsy can
help rule out VOD; however, the 2 conditions may coexist.
Also common during the posttransplantation period are
bacterial infections and septicemia, which can mimic
VOD. Elevations in levels of bilirubin and often alkaline
phosphatase can be seen in sepsis, although the other signs
and symptoms of VOD are less common. Viral hepatitis,
although unusual in this setting, should be considered in the
differential diagnosis, as should cytomegalovirus infections when symptoms appear late. Various fungal infections, especially Candida and Aspergillus infections, are
common in transplant recipients and can result in fungemia
and hepatic infiltration with a laboratory pattern resembling that of VOD. Cyclosporine, the immunosuppressive
agent most commonly used after allogeneic transplantation, various antifungal agents such as fluconazole and
itraconazole, and total parenteral nutrition all can cause
cholestatic hepatitis, and such causes should be ruled out.
In the absence of another proven pathology, a persistent
tumor, especially in the setting of documented pretransplan-
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Hepatic Veno-occlusive Disease
Table 4. Classification System for Severity
of Veno-occlusive Disease
Mild
Patient has no adverse effects from liver disease
Patient requires no treatment of veno-occlusive disease
Illness is self-limited
Moderate
Patient has an adverse effect from liver disease
Patient requires treatment of veno-occlusive disease (such as diuretics
for fluid retention or medication to relieve pain from hepatomegaly)
Severe
Signs and symptoms of veno-occlusive disease do not resolve by
day 100
Patient dies of complications directly attributable to veno-occlusive
disease
tation involvement of the liver by the malignancy, should
be considered in the differential diagnosis. Intra-abdominal
pathologies such as neutropenic colitis also can mimic some
symptoms and laboratory abnormalities seen with VOD.
PROGNOSIS
In most patients (50%-80%), there is a gradual resolution
of the symptoms and signs over a 2- to 3-week period after
onset of disease. The overall mortality from VOD varies
from 20% to 50% in different series. A classification system for the severity of VOD (mild, moderate, and severe)
has been proposed on the basis of the degree of hepatic
dysfunction, the need for therapy, and the outcome (Table
4). Unfortunately this model gives only a retrospective
assessment of the severity and is not useful for making
treatment decisions.
Several prognostic factors help identify patients likely
to do poorly. The degree of bilirubin elevation and the rate
of bilirubin level increase seem to be 2 of the most important predictors. Bearman et al,63 using data from their cohort of patients, proposed a regression model based on
serum bilirubin level and percentage of weight gain to
identify patients at high risk for severe VOD. Since this
system has low sensitivity early in the course of the disease
and was validated only for regimens that include cyclophosphamide, it is not used widely.63 Nevertheless, it is the
only model available at this time for making decisions
regarding timing of intervention, and it may be useful for
clinical trials evaluating preventive strategies. Patients
Table 5. Causes of Death in Severe Veno-occlusive Disease
Hepatic failure directly due to veno-occlusive disease
Renal failure due to hepatorenal syndrome
Respiratory failure due to
Pulmonary veno-occlusive disease
Interstitial pneumonitis (infectious or noninfectious)
Pulmonary hemorrhage
Gastrointestinal bleeding
Congestive heart failure
Mayo Clin Proc, May 2003, Vol 78
with severe VOD develop multiple organ failure and usually die of causes other than hepatic failure (Table 5). Renal
failure is common; pulmonary compromise, which often
requires mechanical ventilation, is also common, as is cardiac failure, which requires inotropic support. Bacteremia
develops in a considerable number of patients and can
contribute to the high mortality seen in these patients. In the
original series of patients reported from Seattle, the mortality rates for those with mild, moderate, and severe VOD
were 9%, 23%, and 98%, respectively.17 Patients requiring
multiple organ support have an extremely poor prognosis
with near-certain death, and physicians in consultation with
family members should seriously consider withdrawing
life support and providing comfort care.
Late complications in those recovering from this illness
are rare. In an extremely small number of patients, the
hepatic damage can persist, and the severe fibrotic changes
that occur can lead to long-term portal hypertension and
esophageal varices.
THERAPY
Several approaches have been tried for the treatment of
VOD, but none has been uniformly effective. The observation of fibrin deposition and immunohistochemical stains
that show factor VIII/von Willebrand factor in the subendothelial region on liver biopsy specimens led to the evaluation of tissue-type plasminogen activator (tPA) for treatment.77 Multiple case reports and small series have reported
resolution of symptoms in patients with established VOD
after therapy with tPA.78-80 Unfortunately, in patients who
usually have thrombocytopenia during this phase of illness,
use of tPA has been associated with an unacceptable rate of
bleeding complications.81 In one of the largest reports
evaluating this therapy, investigators from the Seattle
group reported a high rate of bleeding complications with
only about a third of patients deriving any benefit; investigators did not recommend the use of tPA in these individuals.81 Some studies have suggested that earlier initiation of
therapy may be associated with a better risk-benefit ratio.82
However, note that most patients with VOD improve spontaneously; hence, an earlier initiation of therapy is likely to
include a large number of patients with mild VOD, and the
results become difficult to generalize. Other thrombolytic
agents such as urokinase have been tried but have not been
studied extensively.83
One of the most promising agents tried as therapy for
VOD is defibrotide,84,85 a novel polydeoxyribonucleotide
with adenosine receptor agonist activity. Defibrotide has
been shown to increase PGE2, PGI2, and thrombomodulin
on the endothelial surface; decrease levels of PAI-1; and
increase endogenous tPA levels. Defibrotide has no intrinsic anticoagulant properties and is not associated with any
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risk of bleeding. It is well tolerated, and results from compassionate use studies have shown a 42% survival for
patients with severe VOD.84,85 Results from a multi-institutional study have confirmed the benefit of this agent in the
therapy for established VOD.74
The importance of glutathione in protecting the sinusoidal endothelial cells from chemotherapy and possible
radiation-induced damage led to the evaluation of Nacetylcysteine, a thiol antioxidant. A report of 3 patients
suggested beneficial effects with N-acetylcysteine.86 Highdose corticosteroids have been tried with mixed results.87,88
In one study, early treatment of suspected VOD with highdose methylprednisolone resulted in improvement in
nearly two thirds of patients.87 However, in this study,
patients were treated when they developed hyperbilirubinemia, even in the absence of other criteria for VOD. Other
agents that have been used include PGE1,89,90 glutamine,91,92
and vitamin E1,91,92 but these were used mostly in anecdotal
reports and small series.
Portosystemic shunting has been tried to reduce the
elevated portal pressures seen in patients with severe VOD.
Transjugular intrahepatic portosystemic shunt (TIPS)
placement is an attractive method of creating a shunt in
patients who are unable to undergo open procedures. Animal experiments have provided ample evidence to support
the role of portosystemic shunts in the setting of hepatic
venous outflow obstruction. In canine models, maintenance of portal pressure by shunt creation after hepatic
venous occlusion results in preservation of hepatic energy
metabolism and hepatic function.93 The role of the TIPS
procedure in the management of advanced stages of VOD
remains undefined. Isolated case reports and small case series have shown benefit in a few patients, especially those
with less advanced disease.94,95 Use of the TIPS procedure
has resulted in improved liver function tests and clinical
signs of hepatic failure, and it can control portal hypertension in patients with severe VOD; however, it is unclear
whether these improvements alter the natural course of the
disease. A few patients with hepatic failure secondary to
VOD have undergone liver transplantation with reports of
long-term survival.96,97 This modality remains strictly experimental, however, and few institutions are capable of performing solid organ transplantations in these extremely sick
patients.
Use of charcoal hemofiltration has been reported to be
effective in a small number of patients.98 Its use resulted in
complete reversal of symptoms and signs in patients with
severe VOD and bilirubin levels higher than 30 mg/dL. Our
experience has been 100% mortality for patients whose
bilirubin level exceeded 30 mg/dL. The mechanism behind the beneficial effect is unclear, but further studies are
ongoing.
Hepatic Veno-occlusive Disease
595
In the absence of well-defined treatments, supportive
care remains the cornerstone of care for these patients.
Maintaining intravascular volume and renal perfusion
without causing fluid overload by optimizing sodium restriction and diuretics is extremely important. Patients
should receive transfusions to keep their hematocrit levels
higher than 40%; this would optimize perfusion and help
maintain intravascular volume. The role of albumin or
other colloids is unclear but could be considered in patients
with severe hypoalbuminemia and large third space fluid
accumulations. Low-dose dopamine has been used in patients with VOD and renal insufficiency because the
mechanism of renal dysfunction appears to be hepatorenal
in origin. Avoidance of other hepatotoxic drugs is important in these patients, and infections should be identified
and treated promptly. Therapeutic paracentesis can help
relieve symptoms in patients with large, tense ascites and
may help improve renal function. Also, use of hemodialysis or continuous venous hemofiltration can help with fluid
overload in patients with a poor response to diuretics.
Peritoneovenous shunts, although useful in alleviating refractory ascites, can initiate or exacerbate disseminated
intravascular coagulation. Portosystemic shunts again can
help with portal hypertension and refractory ascites, but
their role is unproved.
PREVENTION
The absence of effective therapies for VOD has spurred
much interest in developing effective preventive strategies
for the disease. Heparin is the best-studied agent used for
prevention. Multiple studies have suggested that low-dose
heparin can decrease the overall incidence of VOD, although its effect on the incidence of severe disease is
unproved.99-101 In a large prospective randomized trial, administration of 100 U · kg–1 · d–1 of unfractionated heparin
started 1 week before transplantation and continued until
day 30 decreased the overall incidence of VOD by nearly
10%.100 Use of low-molecular-weight heparin in place of
unfractionated heparin can decrease the risk of bleeding
episodes and has the advantage of intermittent dosing.101
Low-molecular-weight heparin also may accelerate platelet engraftment, but the mechanism is unclear.102 Ursodeoxycholic acid is administered orally and is usually well
tolerated. At least 2 prospective randomized studies have
shown a decreased incidence of VOD with the prophylactic
use of this agent103,104; another study showed no additional
benefit when ursodeoxycholic acid was combined with
heparin.105 Low-dose PGE1, initiated before conditioning
therapy and continued for 30 days after transplantation,
decreased the incidence of VOD in a study involving patients with acute leukemia who received allogeneic transplants.106 However, other studies have been unable to re-
596
Hepatic Veno-occlusive Disease
produce the results, and PGE1 use has been associated with
considerable toxicity.107 Pentoxifylline, a xanthine derivative, has been studied in prospective trials based on initial
results from small studies.35,108,109 Pentoxifylline is capable
of preventing transcription of tumor necrosis factor α and
stimulates endothelial production of PGI2 and PGE2. These
trials showed no clinically meaningful benefits from the
use of pentoxifylline, and its use was associated with adverse effects. Parenteral glutamine used prophylactically
may decrease the incidence of VOD.110
CONCLUSION
Hepatic VOD is a formidable challenge both for patients
undergoing stem cell transplantation and for their physicians. Hepatic VOD contributes considerably to transplantation-related morbidity and mortality. A high clinical index of suspicion is needed to correctly and consistently
identify patients with VOD. Interventions using therapeutic agents such as defibrotide and N-acetylcysteine appear
to hold promise, and clinical trials currently under way will
provide more answers. Ongoing work, especially the development of new animal models, will help us understand
the pathophysiology of VOD and enable us to develop
effective interventions. Supportive care remains standard
for patients developing VOD, with other interventions
preferably carried out in clinical trial settings.
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