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대한내과학회지: 제 88 권 제 4 호 2015
http://dx.doi.org/10.3904/kjm.2015.88.4.464
ABO 일치 간 이식 후 발생한 Evans syndrome 증례보고
울산대학교 의과대학 서울아산병원 1내과, 2간이식 및 간담도외과
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윤지현 ·안지환 ·조동희 ·김태은 ·송기원 ·이승규 ·이규형
Use of Splenectomy to Treat Evans Syndrome
Following an ABO-Matched Liver Transplant
Ji Hyun Yun1, Jee Hwan Ahn1, Dong Hui Cho1, Taeeun Kim1,
Gi-Won Song2, Sung-Gyu Lee2, and Kyoo-Hyung Lee1
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Department of Internal Medicine and 2Division of Liver Transplantation and Hepatobiliary Surgery, Department of Surgery,
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
Evans syndrome is a rare complication that develops in adults after liver transplantation. The possible etiologies include ABO
mismatch, viral infection, post-transplantation lymphoproliferative disease, graft-versus-host disease, and the use of certain immunosuppressive drugs (e.g., calcineurin inhibitors). Here, we present a case of Evans syndrome that developed after an ABOmatched liver transplant. Glucocorticosteroid, intravenous immunoglobulin, and alternative immunosuppressant therapies all
failed. Weekly rituximab (375 mg/m2) was then administered for 4 weeks. The cytopenia improved transiently after the second dose
of rituximab, but soon worsened again. However, the cytopenia normalized after a splenectomy. (Korean J Med 2015;88:464-468)
Keywords: Autoimmune hemolytic anemia; Idiopathic thrombocytopenic purpura; Liver transplantation; Splenectomy
INTRODUCTION
ported cases [2-7]. First-line ES therapy consists of corticosteroids and intravenous immunoglobulin (IVIG). Immunosup-
Evans syndrome (ES) comprises the triad of autoimmune he-
pressants, rituximab, splenectomy, and chemotherapy can also
molytic anemia (AIHA), immune thrombocytopenia (ITP), and a
be administered when ES is refractory to first-line therapy [1].
positive direct antiglobulin test in the absence of any known un-
Here, we report a case of ES that developed in an ABO-
derlying etiology. ES is a chronic disease that presents with fre-
matched liver transplant patient who was treated successfully
quent exacerbations and remissions [1]. ES following solid or-
with a splenectomy after failing to respond to steroids, IVIG,
gan transplantation is a rare complication, with only a few re-
changes in the immunosuppressant therapy, or rituximab.
Received: 2014. 5. 7
Revised: 2014. 6. 10
Accepted: 2014. 8. 5
Correspondence to Kyoo-Hyung Lee, M.D.
Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu,
Seoul 138-736, Korea
Tel: +82-2-3010-3213, Fax: +82-2-3010-6885, E-mail: khlee2@amc.seoul.kr
Copyright ⓒ 2015 The Korean Association of Internal Medicine
This is an Open Access article distributed under the terms of the Creative Commons Attribution
- 464 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits
unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
－ Ji Hyun Yun, et al. Evans syndrome after liver transplant －
were normal for the post-transplant state.
CASE REPORT
An anemia work-up revealed autoimmune hemolytic anemia
A 51-year-old man visited our emergency room with a 3-day
with the following characteristics: reticulocyte count, 22.31%;
history of nausea, vomiting, general weakness, and dyspnea, but
reticulocyte product index, 2.58; iron, 251 μg/dL; total iron-bind-
no abdominal pain. Six months prior, he had received a liver
ing capacity, 274 μg/dL; ferritin, 874 ng/mL; haptoglobin, < 7.6
transplant from an ABO-matched donor because of hepatitis B
mg/dL; and plasma hemoglobin, 16.6 mg/dL. A peripheral blood
and hepatocellular carcinoma, and he was receiving immunosup-
smear indicated pancytopenia and red blood cell (RBC) aggluti-
pressive therapy with mycophenolate mofetil 250 mg bid and ta-
nation (Fig. 1). The Coombs’ test was IgG- and C3d-positive. A
crolimus 8 mg od. He had been diagnosed with diabetes melli-
bone marrow biopsy revealed erythroid and megakaryocytic hy-
tus 1 year earlier and treated with diet therapy. Tachycardia and
perplasia (Fig. 2). The serum Ebstein-Barr virus (EBV) poly-
pale conjunctivae were noted, but neither cardiac murmur nor
merase chain reaction assay was positive with a measured titer
abnormal breath sounds were observed. There was no abdominal
of 1,746 copies/mL. The patient was PCR-negative for other vi-
tenderness, rebound tenderness, palpable masses, palpable lymph
ruses, including cytomegalovirus (CMV) and parvovirus.
nodes, or hepatosplenomegaly. Laboratory testing revealed se-
Treatment began with 1 mg/kg methylprednisolone, but no
vere anemia, thrombocytopenia, and hyperbilirubinemia: white
cytopenic response was noted 4 days later. The Hb and PLT
3
blood cells, 4,400/mm ; hemoglobin (Hb), 5.8 g/dL; hematocrit,
levels were 6.6 g/dL and 6,000/mm3, respectively. The retic-
3
17.5%; platelets (PLT), 6,000/mm ; aspartate transaminase, 48
ulocyte count, haptoglobin, and LDH were 23.35%, < 7.6 mg/dL,
IU/L; alanine transaminase, 36 IU/L; alkaline phosphatase, 96
and 490 IU/L, respectively. A dose of 0.5 g/kg/day IVIG was
IU/L; total bilirubin, 8.5 mg/dL; direct bilirubin, 4.1 mg/dL; lac-
then given for 4 days, but the cytopenia remained. The EBV
tate dehydrogenase (LDH), 484 (normal 120-250) IU/L; blood
PCR titer turned negative 14 days later, but there was still no
urea nitrate, 29 mg/dL; and creatinine, 1.11 mg/dL. Serum lev-
improvement in the cytopenia and the patient required trans-
els of tacrolimus and mycophenolate mofetil were 4.5 ng/mL
fusion of two units of RBCs and 16 units of PLTs daily. Hb
and 0.2 μg/mL, respectively. There were no significant findings
and PLT levels were 5.7 g/dL and 2,000/mm3, respectively (Fig.
upon chest or abdominal X-ray. Abdominal computed tomog-
3A and 3B). The patient’s reticulocyte count and LDH levels were
raphy revealed a small amount of ascites, but other findings
24.12% and 676 IU/L, respectively (Fig. 3C and 3D). Beginning
Figure 1. Peripheral blood smear, pancytopenia, and red blood
cell agglutination. Wright-Giemsa staining (×400).
Figure 2. Bone marrow biopsy results confirming erythroid and
megakaryocytic hyperplasia. Wright-Giemsa staining (×200).
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－ 대한내과학회지: 제 88 권 제 4 호 통권 제 656 호 2015 －
A
B
C
D
Figure 3. Trends in hemoglobin levels, platelet count, reticulocyte count, and lactate dehydrogenase levels over the course of
treatment. (A) Hemoglobin. (B) Platelet count. (C) Reticulocyte. (D) Lactate dehydrogenase. IVIG, intravenous immunoglobulin.
16 days later, weekly rituximab (375 mg/m2) was administered
DISCUSSION
for 4 weeks. Cytopenia improved without transfusion after the
second dose of rituximab; Hb and PLT levels increased to 8.2
3
ES is a rare disorder characterized by its association with
g/dL and 26,000/mm , respectively, whereas the patient’s retic-
AIHA and ITP, its occasional association with immune neu-
ulocyte count, total bilirubin levels, and LDH levels simulta-
tropenia, and the absence of a known underlying etiology.
neously decreased to 4.99%, 0.8 mg/dL, and 307 IU/L, respec-
First-line ES therapy includes corticosteroids and IVIG. Immu-
tively. After the third dose of rituximab, however, the patient’s
nosuppressive agents like cyclosporin, chemotherapies like vin-
cytopenia worsened. Hb and PLT levels decreased to 7.6 g/dL
cristine and cyclophosphamide, danazol, and therapeutic anti-
3
and 2,000/mm , respectively, while the patient’s reticulocyte
bodies such as rituximab, splenectomy, and plasmapheresis can
count and LDH levels increased to 6.98% and 412 IU/L. Twenty-
be used as second-line therapies [1].
four days later, the immunosuppressant regimen was changed to
ES is a very rare complication of solid organ transplantation
sirulomus 1 mg, but no response was noted. Hb and PLT levels
with only seven reported cases (Table 1): five following liver
3
were 6.7 g/dL and 8,000 /mm , respectively. The patient’s retic-
transplantation; one following a liver and small bowel trans-
ulocyte count and LDH levels increased to 6.98% and 412 IU/L,
plantation; and one following heart transplantation. Five of these
respectively. The patient underwent a splenectomy 45 days later
cases developed in children or infants, and two developed in
and his Hb and PLT levels increased without transfusion.
adults. Four previous ES cases were associated with other
Steroids were successfully tapered off.
medical problems, such as viral infection, post-transplantation
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Polycystic liver disease
Alcoholic liver cirrhosis, hepatocellular
carcinoma
Idiopathic sclerosing
cholangitis
Fulminant liver failure
Giant cell hepatitis
Congenital heart disease
Hirschsprung’s disease
Primary diagnosis
Liver
Liver
Liver
Liver
Liver
Heart
O+/O+
RH incompatibility
Not available
ABO-matched
ABO-matched
Not available
38 yr
67 yr
5 yr
4 yr
5 mon
7 mon
4 yr
Tacrolimus
Tacrolimus
Tacrolimus,
Mycophenolate mofetil
Tacrolimus
Tacrolimus
Cyclosporine
Tacrolimus
7 mon
6 wk
20 mon
7 yr
3 mon
9 yr
4 yr
Blood group Age at Immuno-sup- Time to prerecipient/ transplant
pressants
sentation
donor
Liver + AB+/B+
small
bowel
Graft
type
chronic
GVHD
GVHD
Parvovirus
B19
PTLD
None
EBV
None
None
Association
Steroid
Rituximab
Treatment
8/3,000
6/11,000
Steroid
Rituximab
Steroid
Rituximab
5.2/36,000 Immunoglobulin
Steroid
Rituximab
Cyclophosphamide
Fludarabine
Splenectomy
Cyclosporine
6.7/1,000 Steroid
Immunoglobulin
Rituximab
5.4/26,200 Steroid
Immunoglobulin
Acyclovir
6.1/36,000 Steroid
Immunoglobulin
Rituximab
5/10,000
Hb (g/dL)/
PLT (/μL)
Died of sepsis
Remission in
4 wk
Remission in
40 mon
Remission in
1 mon
Relapse after
18 mon
Response to
rituximab
Remission in
6 mon
Remission in
2 mon
Remission in
3 wk
Relapse after
1 yr
Response to
rituximab
Outcome
Hb, hemoglobin; PLT, platelets; M, male; EBV, Ebstein-Barr virus; F, female; PTLD, post-transplantation lymphoproliferative disease; GVHD, graft-versus-host disease.
M
Au, et al. [2]
F
Miloh, et al.
[8]
M
M
Yokoyama, et
al. [7]
Grosskreutz,
et al. [4]
M
Tubman, et al.
[6]
M
M
Lacaille, et al.
[5]
Domenech, et
al. [3]
Sex
Reference
Table 1. Reported cases of Evans syndrome following solid organ transplantation
－ 윤지현 외 6인. 간 이식 후 발생한 Evans syndrome －
－ The Korean Journal of Medicine: Vol. 88, No. 4, 2015 －
lymphoproliferative disease (PTLD), or graft-versus-host disease
In summary, ES after solid organ transplantation is a rare
(GVHD). EBV and parvovirus B19 were confirmed in two of
hematological complication. Clinicians should remember that ES
these cases in which cytopenia improved after the viral titer
is one of the causes of anemia and thrombocytopenia in solid
turned negative. GVHD developed in two cases. Most of the
organ transplant patients. ES following solid organ transplan-
previous cases of ES achieved remission, but one patient died
tation is usually refractory to steroid therapy and IVIG. Therefore,
from sepsis [2-7].
additional treatment modalities need to be explored.
The etiology of ES following solid organ transplantation re중심 단어: 자가면역 용혈; 특발성 혈소판감소성 자반증;
mains unknown. However, ABO mismatch, viral infection, PTLD,
GVHD, and complications from immunosuppressive drugs are
간이식; 비장절제술
possible causes. ABO mismatch can also cause alloimmunity
[4,5]. Viral infections such as EBV, CMV, and parvovirus B19
are other possible causes. Molecular mimicry and cross-reactivity with viral antibodies might influence the RBC or PLT
antigens [3,7,8]. Immunosuppressants like calcineurin inhibitors
(CNIs) can also induce ES. CNIs like cyclosporine and tacrolimus are commonly used as immunosuppressants to prevent graft
rejection and are associated with some cases of AIHA that develop following solid organ transplantation. AIHA has been
cured after changing the immunosuppressive agent to an mTOR
inhibitor such as sirolimus [9]. This mechanism might also lead
to the development of ES following solid organ transplantation.
In our case, the donor was ABO-matched and there was no evidence of PTLD or GVHD. The EBV PCR titer was positive,
but cytopenia persisted after the EBV PCR titer turned negative.
Tacrolimus was used for immunosuppression, but the change to
sirolimus was ineffective.
In all seven reported cases of ES that developed after solid
organ transplantation, corticosteroids and IVIG were administered as the first-line therapy. However, this disease was refractory to first-line therapy in all except one case that developed
8 months after liver transplantation. Rituximab was given as the
second-line therapy in six cases, and remission was achieved in
four cases. Fludarabine, splenectomy, and cyclosporine were
used in the rituximab-refractory patients and a response was observed after a splenectomy and cyclosporine intervention [2-7].
This indicates that ES following solid organ transplantation is
usually refractory to corticosteroids and IVIG and other treatment modalities should be considered, such as rituximab, splenectomy, or different immunosuppressants.
- 468 -
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Evans’ syndrome complicating chronic graft versus host
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3. Domenech C, Mialou V, Galambrun C, et al. Successful
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4. Grosskreutz C, Gudzowaty O, Shi P, Rodriguez-Laiz G,
Malone A, Isola L. Partial HLA matching and RH incompatibility resulting in graft versus host reaction and Evans
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