Download Hepatitic variant of graft-versus-host disease after

CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Hepatitic variant of graft-versus-host disease after donor lymphocyte infusion
Görgün Akpek, John K. Boitnott, Linda A. Lee, Jason P. Hallick, Michael Torbenson, David A. Jacobsohn, Sally Arai,
Viki Anders, and Georgia B. Vogelsang
Graft-versus-host disease (GVHD) of the
liver is characterized by bile duct damage
and portal lymphocytic infiltrate. We report acute hepatitislike presentation of
GVHD after donor lymphocyte infusion
(DLI). Between April 1998 and September
2001, 73 patients received 94 DLI treatments. Liver GVHD developed after DLI in
22 (30%) patients whose median age was
43 years (range, 21 to 61 years). Onset of
liver dysfunction was at 35 days (range,
11 to 406 days) after DLI. Fifteen patients
underwent liver biopsy, and the diagnosis
of liver GVHD was confirmed in 13 (87%)
patients. After viral hepatitis and recent
drug exposure were excluded, 11 (50%)
patients were given a diagnosis of a hepatitic variant of GVHD based on histologic
evidence of lobular hepatitis (n ⴝ 5), elevation of maximum serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level more than 10 times the
upper normal limit (n ⴝ 9), or both. There
was a significant difference in maximum
ALT (P ⴝ .002) and AST (P ⴝ .01) level
between the hepatitic-variant and classi-
cal GVHD groups. GVHD progressed in 14
(64%) patients, and 10 patients died after
a median follow-up of 221 days (range,
31-1284 days). These observations suggest that GVHD that occurs after DLI may
have distinct clinical features. Hepatiticvariant GVHD should be considered in
the differential diagnosis in DLI recipients
with unexplained hepatitis. (Blood. 2002;
100:3903-3907)
© 2002 by The American Society of Hematology
Introduction
Cholestatic liver abnormalities in an allograft recipient with
clinical or biopsy evidence of cutaneous or intestinal graft-versushost disease (GVHD) are usually attributable to liver GVHD.1
Onset usually coincides with myeloid engraftment after transplantation, and progressive jaundice is the most common presenting
feature of liver involvement.2 The serum alkaline phosphatase
(ALP) level, a sensitive diagnostic marker for liver GVHD,3 rises
steadily, as much as 20-fold above normal, with a parallel rise in
serum bilirubin level. Serum levels of aspartate aminotransferase
(AST or SGOT) and alanine aminotransferase levels (ALT or
SGPT) are frequently elevated, especially during the early stages of
GVHD, but they almost never are more than 10 times higher than
normal.2 Liver biopsy is important to confirm the diagnosis and to
exclude other treatable causes of liver dysfunction, such as drug
effects, viral infection, or fungal infection. Typical liver GVHD is
characterized by lymphocytic infiltration of small bile ducts with
nuclear pleomorphism and epithelial cell dropout.4,5 The extent of
both apoptosis and dropout cells serves to distinguish acute liver
GVHD from the other causes of liver dysfunction.4
Recently, an unusual form of liver GVHD has been described.
Strasser et al6 report their observations in 14 patients in whom
chronic GVHD of the liver was accompanied by marked elevations
of serum aminotransferase levels, clinically resembling acute viral
hepatitis.6 Similarly, Fujii et al7 report a patient with liver GVHD,
thought to be acute hepatitis, 23 days after allogeneic peripheral
blood stem cell transplantation (SCT).7 In another case report,
chronic GVHD, also thought to be acute hepatitis, 36 weeks after
matched-unrelated allogeneic SCT for chronic myelogenous leuke-
mia was described.8 In the present case series of 22 patients, we
report our clinical observations of this hepatitic variant of liver
GVHD that occurred after donor lymphocyte infusion (DLI).
From the Department of Oncology, Pathology, and Medicine, The Johns
Hopkins University School of Medicine, Baltimore, MD.
Center, Bunting and Blaustein Cancer Research Bldg, 2M02G, The Johns
Hopkins University School of Medicine, 1650 Orleans St, Baltimore, MD 212311000; e-mail: [email protected].
Submitted March 27, 2002; accepted July 3, 2002. Prepublished online as
Blood First Edition Paper, July 18, 2002; DOI 10.1182/blood-2002-03-0857.
Patients, materials, and methods
We retrospectively reviewed the data on 22 patients with clinical and
laboratory evidence of liver GVHD that developed after DLI. Three
additional patients were not included in this series because of incomplete
information. Patients were treated with DLI after obtaining an informed
consent approved by The Johns Hopkins University School of Medicine
institutional review board. Patients received diagnoses of liver GVHD if
they had progressive increases in serum liver enzyme levels after DLI and
no other causes could be identified by history, physical examination, and
standard screening tests. Patients had to have no history of new drug
exposure and no recent change in the dose or schedule of their routine
medications. Routine bacterial and fungal cultures were obtained to rule out
ongoing subtle infection. The possibility of viral hepatitis caused by
hepatitis A (HAV), B (HBV), C (HCV), herpes simplex (HSV), and
varicella zoster (VZV) was ruled out by standard serologic tests. In the
appropriate hosts, evidence of primary infection or reactivation of HSV,
cytomegalovirus (CMV), or adenovirus was sought. Polymerase chain
reaction (PCR) analysis was not routinely performed. Radiologic studies,
including abdominal ultrasound or computed tomography (CT), were
conducted to rule out the presence of an obstructive or intraparenchymal
lesion. As a prerequisite for inclusion in this analysis, patients had to be
starting a new immunosuppressive treatment or continuing an existing
regimen for other manifestations of GVHD that was modified after the liver
Presented in the poster session at the 2002 Tandem BMT Meeting, February
21-26, 2002; Orlando, FL.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
Reprints: Georgia B. Vogelsang, Sidney Kimmel Comprehensive Cancer
© 2002 by The American Society of Hematology
BLOOD, 1 DECEMBER 2002 䡠 VOLUME 100, NUMBER 12
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AKPEK et al
Figure 1. Histologic changes of liver GVHD. Characteristic
histology of classical liver GVHD with bile duct lymphocytic
infiltrates and injury. (A) Portal lymphocytic inflammation is also
present. (B) Lobules show mild hemosiderin accumulation with no
significant inflammation. (C) Hepatitic-variant liver GVHD demonstrates only mild chronic inflammation of the portal tracts, with
minimal bile duct changes. (D) In contrast, the lobules show
definite hepatitis. Original magnification ⫻ 25; hemotoxyleneeosine staining.
GVHD diagnosis. GVHD of the skin, gut, eye, or mouth was diagnosed in
all patients based on established clinical and histologic criteria before
(n ⫽ 4) or at (n ⫽ 18) the onset of liver GVHD.
Fifteen (68%) patients underwent liver biopsy to rule out viral hepatitis
and to confirm the diagnosis of GVHD. Based on the following histologic
criteria, 2 subtypes of liver GVHD were defined. The first subtype was
based on features consistent with classical GVHD if bile duct epithelial
injury and portal lymphocytic infiltration occurred (Figure 1A). In this
subtype, hepatocellular structure had to be relatively preserved with no
significant inflammation (Figure 1B). The second subtype was based on
features consistent with hepatitic variant of GVHD if bile duct injury was
relatively mild (Figure 1C) and lobular hepatitis was the predominant
histologic finding (Figure 1D). Liver biopsy specimens were not sent for
viral culture. Biopsy specimens showing the histology of lobular hepatitis
were evaluated for cytomegalovirus infection by immunohistochemical
staining. Immunostaining for HSV and adenovirus was performed when
clinically indicated. The diagnosis of hepatitic-variant GVHD was based on
the presence of lobular hepatitis or on marked (more than 10 times the upper
normal limit [UNL]) elevation of serum aminotransferase (ALT or AST)
levels. The Wilcoxon rank sum test was used to compare maximum serum
liver enzyme levels that included ALP, ALT, AST, total bilirubin, and direct
bilirubin between patients with classical liver GVHD and those with
hepatitic-variant GVHD.
Results
were 372 U/L (range, 106-2910 U/L), 2.7 mg/dL (range, 0.4-32
mg/dL), 1.2 mg/dL (range, 0.1-26.5 mg/dL), 410 U/L (range,
103-1540 U/L), and 245 U/L (range, 61-1256 U/L), respectively
(Table 2). Maximum levels of ALT or AST were more than 10 times
Table 1. Patient characteristics
n (%)
Male/female
Median age, y
Underlying disease
Chronic myelogenous leukemia
4 (18)
Acute leukemia
8 (36)
Lymphoma
3 (14)
Multiple myeloma
6 (27)
Other
1 (5)
Disease status
Chronic phase/complete remission
Relapse/refractory
7 (32)
15 (68)
BMT data
Bone marrow is source of graft
22 (100)
Busulfan/cyclophosphamide
20 (90)
Matched-related donor
20 (90)
Matched-unrelated donor
1 (5)
Mismatched-related donor
1 (5)
GVHD prophylaxis
Cyclosporine (CsA)
Between April 1998 and September 2001, 73 patients received 94
DLI treatments. Twenty-two (30%) patients (13 men, 9 women;
age range, 21 to 61 years; median, 43 years) developed liver
GVHD after receiving DLI with (n ⫽ 7) or without (n ⫽ 15) prior
chemotherapy. Patient characteristics are summarized in Table 1.
Ten (45%) patients had prior acute GVHD after transplantation,
and 2 of them had liver involvement. No patients were taking
immunosuppressive therapy before DLI. Ten (45%) patients received CD3⫹ cells at a dose of less than 5 ⫻ 107, and in 12 (55%)
patients the doses were 108 cells/mm3 or greater. For the entire
group, median interval from the time of DLI to the onset of liver
dysfunction was 35 days (range, 11 to 406 days). Liver GVHD with
(n ⫽ 18) or without (n ⫽ 4) skin or gut GVHD was diagnosed in a
median of 4 days (range, 0 to 25 days) after the onset of liver
dysfunction, which was defined by liver function test results greater
than 2 times the UNL.
For the entire group, the median peak serum levels of alkaline
phosphatase (ALP), total bilirubin, direct bilirubin, ALT, and AST
13/9
43 (range, 21-61)
13 (59)
Tacrolimus (FK-506)
5 (23)
CsA ⫹ prednisone/methotrexate
4 (18)
T-cell depletion
Acute GVHD after BMT
Liver involvement
Time from BMT to DLI, d
18 (82)
10 (45)
2 (20)
309 (range, 73-2617)
Date of DLI (4/98-9/01)
1998 or earlier
5 (23)
1999–2000
9 (41)
2001
8 (36)
DLI indication
Hematologic relapse
Cytogenetic relapse or preemptive DLI
16 (73)
6 (27)
DLI type
DLI alone
Chemotherapy followed by DLI
15 (68)
7 (32)
Dose of T cells infused
5 ⫻ 107 or fewer
10 (45)
1 ⫻ 108 or more
12 (55)
BLOOD, 1 DECEMBER 2002 䡠 VOLUME 100, NUMBER 12
HEPATITIC VARIANT OF GVHD
Table 2. Serum liver tests
No. patients
Median (range)
Normal
10⫻ UNL
or less
More than
10⫻ UNL
At GVHD
ALP
305 (106-1967)
2
18
2
T bili
1.3 (0.4-7.0)
11
11
0
D bili
0.5 (0.1-5.6)
5
11
6
AST
191 (22-1256)
2
17
3
ALT
250 (54-1540)
0
18
4
ALP
372 (106-2910)
1
16
5
T bili
2.7 (0.4-32.0)
8
8
6
D bili
1.2 (0.1-26.5)
3
10
9
AST
245 (61-1256)
0
18
4
ALT
410 (103-1540)
0
15
7
Peak values
T bili indicates total bilirubin; and D bili, direct bilirubin.
the UNL in 11 patients (Tables 2 and 3). Standard serologic test
results were negative for HBV (n ⫽ 13), HBC (n ⫽ 13), HAV
(n ⫽ 4), HSV (n ⫽ 2), VZV (n ⫽ 2), CMV (n ⫽ 2), as were blood
CMV early antigen findings (n ⫽ 12). Blood viral cultures for
CMV (n ⫽ 12), HSV (n ⫽ 7), and adenovirus (n ⫽ 6) and PCR
studies for hepatitis C (n ⫽ 3) and adenovirus (n ⫽ 1) were also
negative (n ⫽ number of patients).
Liver biopsy specimens were obtained from 15 patients in a
median of 6 days (range, 1-67 days) after the onset of liver
dysfunction. Thirteen of 15 (87%) specimens revealed histologic
features consistent with liver GVHD and showing varying degrees
of bile duct epithelial damage with or without portal lymphocytic
infiltration. Histopathologic features of lobular hepatitis were
present in 5 (33%) patients in whom immunostain findings for
CMV (n ⫽ 5), HSV (n ⫽ 2), and adenovirus (n ⫽ 1) were negative. Of note, the lymphocytes infiltrating the hepatocellular
parenchyma were CD3⫹ T cells in 2 samples studied. Other
histopathologic features variably present in liver biopsy specimens
included intralobular bile stasis, prominent hepatocellular hemosiderin accumulation, fat accumulation, mild to moderate portal or
sinusoidal fibrosis, mild focal cholangitis, venous endothelialis,
hepatocellular dropout, atrophy, or swelling, increased hepatocellular and nuclear polymorphism, focal hepatic necrosis, and small
nodules of histiocytosis.
After the exclusion of viral infection and drug history, 11 (50%)
patients received a diagnosis of hepatitic variant of liver GVHD.
Table 3. Description of 11 patients with hepatitic-variant liver GVHD
Patient
ALP*
AST/ALT*
Total
bilirubin/direct
bilirubin*
1
106
506/442
0.8/0.2
2
1262
402/825
3
820
4
783
5
GVHD
outcome
Alive
N/A
Improved
Yes
2.8/1.4
N/A
Improved
Yes
438/772
2.6/1.5
Present
Improved
Yes
307/1148
5.1/4.2
Absent
Worsened
Yes
382
226/318
1.1/0.5
Present
Improved
Yes
6
164
1256/245
2.1/1.2
Absent
Worsened
Yes
7
362
18.4/17.4
Absent
Worsened
No
8
158
246/411
1.0/0.9
Present
Worsened
9
354
383/828
19.2/6.5
Present
Worsened
10
1540
918/1540
1.1/0.3
Present
11
239
245/930
9.0/6.9
Absent
80/1495
Lobular
hepatitis
3905
Characteristic features of these 11 patients are summarized in Table
3. Median ALP, ALT, AST, total bilirubin levels, and direct
bilirubin levels in the hepatitic-variant group were 362 U/L, 825
U/L, 383 U/L, 2.6 mg/dL, and 1.4 mg/dL, respectively. There were
significant differences in peak levels of ALT (P ⫽ .002) and AST
(P ⫽ .01) between patients with hepatitic and those with classical
liver GVHD as determined by the Wilcoxon rank sum test (Table
4). Histologic features of the liver biopsy specimens obtained from
2 patients in this series are shown in Figure 1A-B (classical) and
Figure 1C-D (hepatitic variant). Alkaline phosphatase, ALT, AST,
and total bilirubin levels were 1980 U/L, 394 U/L, 199U/L, 11
mg/dL for classical and 158 U/L, 411 U/L, 246 U/L, and 1 mg/dL
hepatitic-variant GVHD in these 2 patients, respectively. Median
time from initial liver dysfunction to liver biopsy was 2 days
(range, 1 to 57 days) for 5 patients who had histologic features of
lobular hepatitis and 15 days (range, 3-67 days) for 10 patients who
did not have this histologic component. Chemotherapy treatment
before DLI and T-cell dose was not associated with the occurrence
of hepatitic GVHD.
Patients were treated with high-dose combined immunosuppressive therapy that resulted in improvement or resolution of GVHD
in 8 (36%) patients. Lichenoid chronic GVHD developed in 15
(68%) patients in a median of 27 days (range, 0 to 324 days) after
the diagnosis of acute GVHD after DLI. Four (27%) of these
patients had chronic GVHD at the initial presentation. As of the
date of analysis, the median follow-up for all patients was 221 days
(range, 31-1284 days). Ten (45%) patients died. Progressive
GVHD was complicated by systemic bacterial or fungal infection
and death in 6 patients. One patient in the classical liver GVHD
group died of hepatic failure. Two patients died of relapse of
underlying hematologic malignancies, and one died of alveolar
hemorrhage. Nine patients in the hepatitic-variant group and 3
patients in the classical liver GVHD group remain alive.
Discussion
Although DLI may provide curative therapy through a graft-versustumor effect, complications result in significant morbidity and
mortality. Prominent among these complications is acute and
chronic GVHD, major factors affecting the outcome in these
patients. In general, approximately 60% of the patients have acute
(grade 2 or higher) or chronic GVHD, and half of these patients die
of GVHD-related complications.9-11 Besides its high incidence and
severity, DLI-GVHD appears to have distinct clinical features. In a
recent case report, post-DLI chronic GVHD associated with
polymyositis, polyserositis with a large pericardial effusion, and
constrictive pericarditis was described.12 We have seen numerous
Table 4. Comparison of serum liver enzymes between classical and hepatitic
liver GVHD
Median (10th percentile, 90th percentile)
Classical liver GVHD
n ⫽ 11
Hepatitic-variant GVHD
n ⫽ 11
P
Alkaline phosphatase
542 (271, 1980)
362 (158, 1262)
NS
No
ALT
315 (142, 411)
825 (318, 1495)
.002
No
AST
190 (78, 289)
383 (226, 918)
.01
Worsened
Yes
Total bilirubin
5.1 (0.5, 31.9)
2.6 (1.0, 18.4)
NS
Worsened
Yes
Direct bilirubin
2.1 (0.2, 26.3)
1.4 (0.3, 6.9)
NS
N/A indicates not applicable.
*Maximum values, upper normal limits: ALP, ⬍127 U/L; AST/ALT, ⬍47/53; total
bilirubin/direct bilirubin, ⬍ 1.2/0.3.
Numbers in parentheses represent 10th percentile and 90th percentile,
respectively.
NS indicates not significant by Wilcoxon rank-sum test.
3906
AKPEK et al
DLI patients who have symptoms of acute and chronic GVHD or
who experience rapid transition from acute to chronic GVHD
(G.B.V., G.A., unpublished, 1997-2002). Although de novo chronic
GVHD developed in some patients shortly after DLI, others had an
unusual presentation without skin involvement. The clinical course
of DLI-GVHD seems more complicated and prolonged, possibly
because of its refractoriness to the standard treatments compared
with SCT-GVHD. DLI patients also can have advanced-stage
GVHD resulting in high mortality (G.B.V., unpublished observation, June 2001). Other groups have begun to recognize unusual
presentations of DLI-GVHD with predominant gastrointestinal
involvement.
In the present study, we report an unusual presentation of liver
GVHD (hepatitic variant) in DLI recipients. Given the similar presentations reported after marrow or blood stem cell transplantation, it does not
appear to be unique to DLI. However, hepatitic-variant GVHD seems
more prevalent among DLI recipients. Because of the limitations of
serologic studies in immunosuppressed patients, the low diagnostic
yield of viral cultures, and the long turnaround time, liver biopsy
specimens were obtained from 15 patients to rule out viral hepatitis and
to confirm the diagnosis of liver GVHD. Although liver biopsy is useful
for diagnosis, 2 patients had markedly elevated ALT and AST levels but
did not show the histology of lobular hepatitis, likely reflecting the
imperfect correlation between liver biopsy and serum ALT and AST
levels.4,5 Therefore, we included marked (more than 10 times UNL)
elevation of serum aminotransferase levels in the definition of hepatitic GVHD.
One possible limitation of the present study is the lack of a
uniform evaluation using more sensitive molecular methods to rule
out the viral etiology. Although it would be complementary,
evaluating the liver biopsy specimens for HBV or HCV by PCR is
not routine in our institution for the diagnosis of viral hepatitis.
Culture of liver tissue is not a sensitive way to identify other viral
infections either. These are probably best eliminated by histologic
examination (eg, CMV, HSV), immunostaining of liver tissue (eg,
adenovirus), and serologic testing. Despite the absence of a
relevant history, drug-induced liver damage cannot be completely
ruled out because all patients were taking their routine medications.
Nonetheless, overall clinical and laboratory features of this cohort
of patients were more consistent with liver GVHD than viral or
drug-induced hepatitis.
It is difficult to explain why some of the DLI recipients had this
unusual hepatitis presentation. The sample size was too small to
identify any clinical or laboratory correlate with this presentation.
It has been suggested that the duration of GVHD preceding biopsy
influences the histologic features. Shulman et al4 studied the liver
histology from patients with GVHD at different intervals after
allogeneic bone marrow transplantation (BMT). Although biopsy
specimens obtained before day 35 showed frequent acidophilic
bodies and infrequent bile duct changes, biopsy specimens from
days 35 to 90 after transplantation had more frequent bile duct
lymphocytic infiltration and disruption, and biopsy specimens from
patients with chronic GVHD (beyond day 90) showed more
frequent portal fibrosis and bile duct atrophy and loss. In the
present study, the interval between the onset of liver dysfunction
and the time of liver biopsy was shorter in patients who had the
hepatitic variant of GVHD than in those who did not. However, the
presence of lobular hepatitis did not appear to be related to the
timing of liver biopsy. Although lobular hepatitis accompanied by
mononuclear cells and eosinophils into the portal triads can be seen
during the early stage of liver GVHD, bile duct injury is not a
typical histologic feature of this stage.5,13 Bile duct injury with or
BLOOD, 1 DECEMBER 2002 䡠 VOLUME 100, NUMBER 12
without portal inflammation was already visible in varying degrees
in 4 of the 5 patients reported here. In addition, the degree of
lobular hepatitis was far greater than typically seen in early stages
of liver GVHD. Serum ALT and AST levels were more than 10
times the UNL in 3 of these patients. Finally, GVHD of skin or gut
was present before liver biopsy was performed.
Unfortunately, the outcome for patients with liver GVHD was poor
in this series of 22 DLI recipients. Approximately half the patients died
after a median follow-up of less than 1 year. The major cause of death
was progressive GVHD complicated by infections or hepatic failure. Of
note, 3 of the 5 patients with lobular hepatitis had progression of liver
GVHD. Although fewer patients with hepatitic-variant GVHD died than
without the variant, the numbers are too small to draw any conclusion in
terms of prognostic effect of the variant. In general, the treatment
options for advanced liver GVHD are limited. In a large retrospective
series, only 30% of patients with liver GVHD had resolution of liver
abnormalities after initial treatment.14 Of patients with liver GVHD who
do not respond to initial treatment, secondary treatment results in
improvement or resolution of liver disease in 25% of patients.15
Ursodeoxycholic acid, in conjunction with standard immunosuppression therapy, may be useful in treating these patients. It has been
suggested that UDCA reduces the class 1 human leukocyte antigen
(HLA) expression, target for CD8⫹ T cells, on hepatocytes.16
The molecular events leading to apoptosis in liver GVHD after
stem cell transplantation are not well understood, but they involve
donor T-cell activation and proliferation leading to tissue injury, in
part by direct cytotoxicity through the Fas/Fas-ligand pathway.
Cytotoxic T cells and natural killer cells damage target tissue by
release of Fas-ligand and tumor necrosis factor–␣ (TNF-␣).17,18 A
recent report suggests that the release of preformed FasL by
infiltrating donor T cells may contribute to recipient tissue damage
during the pathogenesis of acute GVHD.19 Lately, there has been a
great deal of interest in using neutralizing anti-FasL monoclonal
antibodies (mAbs) alone or in combination with anti–TNF-␣ in the
treatment of acute GVHD in mice models.20,21
Other studies in murine transplantation models suggest that
macrophage inflammatory protein-1 (MIP-1)–induced migration of
CCR5-expressing CD8⫹ T cells into portal areas may have a role in
GVHD-associated liver injury.22 Serody et al23 also noted the
increased expression of MIP-1␣ associated with the transfer of
allogeneic T cells, leading to enhanced recruitment of CD8⫹, but
not CD4⫹ donor T cells in liver. Some evidence indicates that liver
injury in chronic GVHD may result from the participation of donor
CD4⫹ and CD8⫹ T cells.24
Data on the pathogenesis of GVHD occurring after DLI is even
more limited. The often distinct presentation and the rapid clinical
course of GVHD after DLI suggest that the immunopathophysiologic mechanisms of DLI-GVHD may be different from those of
SCT-GVHD. This difference might be caused by the absence of
initial inflammatory reactions to the conditioning treatment in
DLI-GVHD. Preliminary data suggest that the ratio of Th1/Th2
cytokine expression is progressively shifted toward a Th2 cytokine
(interleukin-10) predominance, similar to that for autologous
GVHD. On the other hand, murine studies also showed that
alloreactive T-cell proliferation after DLI was delayed (A. Hess, L.
Luznik, unpublished data, June 2002).
Based on these clinical observations, we conclude that hepatiticvariant GVHD can be seen after DLI; therefore, it should be
considered in the differential diagnosis in DLI recipients with
unexplained hepatitis. The unusual manifestations and the relatively rapid clinical course of GVHD after DLI may result from
distinct pathogenetic mechanism(s) that warrants study.
BLOOD, 1 DECEMBER 2002 䡠 VOLUME 100, NUMBER 12
HEPATITIC VARIANT OF GVHD
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