405 □ CASE REPORT □ Fulminant Hepatic Failure Caused by Adenovirus Infection Mimicking Peliosis Hepatitis on Abdominal Computed Tomography Images after Allogeneic Hematopoietic Stem Cell Transplantation Kiriko Terasako 1 , Kumi Oshima 1 , Hidenori Wada 1 , Yuko Ishihara 1 , Koji Kawamura 1 , Kana Sakamoto 1 , Masahiro Ashizawa 1 , Miki Sato 1 , Tomohito Machishima 1 , Hideki Nakasone 1 , Shun-ichi Kimura 1 , Misato Kikuchi 1 , Shinya Okuda 1 , Shinichi Kako 1 , Rie Yamazaki 1 , Kengo Takeuchi 2 , Junji Nishida 1 , Shigeki Yamada 3 , Osamu Tanaka 4 and Yoshinobu Kanda 1 Abstract Disseminated adenovirus disease after allogeneic hematopoietic stem cell transplantation (HSCT) is lethal in most cases, especially when it develops as fulminant hepatic failure. We encountered a patient who devel- oped fulminant hepatic failure caused by adenovirus infection. She did not show manifestations of graft- versus-host disease and the results of serum tests for viral infection were all negative. Abdominal computed tomography (CT) findings were consistent with peliosis hepatitis. She died of fulminant hepatic failure, how- ever, and pathological examinations of the liver specimen obtained after her death revealed adenovirus infec- tion. In this report, we review the clinical characteristics and imaging findings of fulminant hepatic failure caused by adenovirus infection. Key words: fulminant hepatic failure, adenovirus, hematopoietic stem cell transplantation, peliosis hepatitis (Intern Med 51: 405-411, 2012) (DOI: 10.2169/internalmedicine.51.6432) Introduction Adenovirus infection after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with high transplant-related mortality. Adenovirus infection is not in- frequently observed after allogeneic HSCT. In 1980’s, ade- novirus was reported to be isolated from approximately 5% of patients undergoing bone marrow transplantation (1). Re- cently, weekly monitoring by enzyme-linked immunoassay (ELISA) for adenovirus antigen and polymerase chain reac- tion (PCR) for adenovirus DNA revealed that the incidence of adenovirus infection was 29% (2). The results of nested PCR for adenovirus DNA using samples from peripheral blood (PB), stool, urine, and throat were positive in 27% of patients after allogeneic HSCT (3). Another retrospective study reported that adenovirus infection was detected in 11.5% of allogeneic HSCT recipients (4). The risk factors for the development of adenovirus infection were graft- versus-host disease (GVHD) and the presence of adenovirus antibody in the donor (1, 2). The clinical course of adenovirus infection ranges from subclinical reactivation to fatal disseminated adenovirus dis- ease. Shields et al (1) isolated adenovirus from 51 of 1,051 patients undergoing marrow transplantation and invasive in- fection was histologically confirmed in 10 of the 51 pa- tients, including those with hepatitis. We encountered a pa- tient who developed fulminant hepatic failure caused by 1 Division of Hematology, Saitama Medical Center, Jichi Medical University, Japan, 2 Department of Pathology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Japan, 3 Department of Pathology, Saitama Medical Center, Jichi Medical University, Japan and 4 De- partment of Radiology, Saitama Medical Center, Jichi Medical University, Japan Received for publication August 22, 2011; Accepted for publication November 7, 2011 Correspondence to Dr. Yoshinobu Kanda, [email protected]
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405
□ CASE REPORT □
Fulminant Hepatic Failure Caused by Adenovirus InfectionMimicking Peliosis Hepatitis on Abdominal Computed
Tomography Images after Allogeneic HematopoieticStem Cell Transplantation
Kiriko Terasako 1, Kumi Oshima 1, Hidenori Wada 1, Yuko Ishihara 1, Koji Kawamura 1,
Kana Sakamoto 1, Masahiro Ashizawa 1, Miki Sato 1, Tomohito Machishima 1,
Intranuclear inclusions with characteristic Cowdry bodies
and chromatin margination were found in some hepatocytes.
Immunostaining for adenovirus (MAB805, blend of clones
20/11 and 2/6; CHEMICIN International Inc., Temecula,
CA, USA) showed diffusely positive nuclear staining, while
those for CMV and EB virus were negative.
Discussion
The main causes of liver injury after HSCT vary depend-
ing on the timing after SCT. Sinusoidal obstruction syn-
drome and drug-induced hepatotoxicity are frequently ob-
served in the first few weeks after SCT. Subsequently, acute
GVHD, viral infection, chronic GVHD, and nodular regen-
erative hyperplasia develop (10). Adenovirus is one of the
causes of fulminant hepatic failure after HSCT. Acute or ful-
minant adenovirus hepatic failure is not an uncommon com-
plication after HSCT. As shown in Table 1, however, there
are differences in the timing after SCT, symptoms, and
speed of progression.
Adenoviral disease can be diagnosed by histology, im-
munocytochemistry and culture of biopsied specimen. How-
ever, its diagnosis is hampered by the difficulty to obtain an
appropriate specimen. In particular, liver biopsy is difficult
to perform due to the high risk of bleeding. Therefore, im-
aging studies may be useful if there are some specific find-
ings for adenovirus hepatitis. To date, there have been few
reports on the imaging findings of severe liver injury after
HSCT. SOS after HSCT shows specific Doppler sonography
findings, including reversed or “to and fro” flow in the por-
tal vein and/or a decreased flow in the portal vein (11).
However, no specific findings on imaging studies have been
reported thus far about adenovirus hepatitis after HSCT. As
shown in Table 2, the results of imaging studies of adenovi-
rus hepatitis after HSCT have been described in 3 patients.
One of the 3 patients showed diffuse nonspecific changes by
ultrasound and magnetic resonance scans of the liver (12),
Intern Med 51: 405-411, 2012 DOI: 10.2169/internalmedicine.51.6432
408
Figure 2. Abdominal CT findings. (A) Arterial phase of abdominal CT with contrast enhance-ment. (B) Portal venous phase of abdominal CT with contrast enhancement. Multiple oval-shaped low-density lesions from a few millimeters to about 3 cm in diameter are observed. These lesions show slow but homogeneous centripetal enhancement.
A B
Figure 3. Histopathological examinations of the liver specimen. (A) Hematoxylin and Eosin stain-ing (10×0.45), (B) Hematoxylin and Eosin staining (40×0.95) and (C) immunohistochemistry staining for adenovirus proved nuclear staining. (MAB805 40×0.95).
while the other 2 showed no abnormality (13, 14). With re-
gard to solid organ transplantation recipients, Gupta et al.
reported adenoviral hepatitis in a cardiac transplant recipi-
ent (15). Abdominal CT scan showed multiple indeterminate
low-attenuation masses in the liver. Similarly, Saad et al de-
scribed a patient with adenovirus hepatitis after an ortho-
topic liver transplantation (16). CT scans of the liver showed
multiple low-density ill-defined lesions. Among hematologi-
cal disorder patients other than HSCT recipients, the ab-
dominal CT scan of an 84-year-old man with B-cell lym-
phoma who developed adenovirus-induced acute liver failure
showed innumerable small hypoattenuating lesions, which
probably corresponded to the areas of hepatic necrosis ob-
served in autopsy (Table 3) (17). Hough et al reported 3
acute lymphoblastic leukemia patients with hepatomegaly
and abnormal findings by ultrasound scan (18).
Intern Med 51: 405-411, 2012 DOI: 10.2169/internalmedicine.51.6432
409
Table 1. Characteristics and Outcomes of Adult Allogeneic HSCT Patients with Adenovirus Fulminant Hepatic Failure
No. Age Sex Disease Diagnosticapproach
Diagnostic sites Serotype Onset Image Other organ involvement
AcuteGVHD
Treatment Outcome Use of steroid
Ref
1 24 F AML His Liver 1 N.A. Noimage
N.A. + N.A. Dead N.A. [1]
2 22 M CML His Liver 2 Day 136
Noimage
- GradeIII
IVIG Dead + [20]
3 21 M ALL His,Cul Liver , blood N.A. 4months
Noimage
- GradeIII
N.A. Dead N.A. [21]
4 23 N.A. CML Cul Liver 1 Day 112
Noimage
- - Cidofovir, IVIG Alive - [22]
5 39 M ALL Cul Sigmoid N.A. Day 68 Noimage
Colitis - Cidofovir, IVIG Dead - [22]
6 43 M AML Cul Liver, BAL 1 Day 187
Noimage
Pneumonia N.A. Cidofovir, IVIG Alive + [22]
7 73 M AML Cul Sigmoid 1 Day 64 Noimage
Colitis + Cidofovir, IVIG Dead + [22]
8 35 F MDS PCR Blood, BAL 3 and 34
Day 45 Noimage
Nephritis,pneumonia, colitis
- Ganciclovir, IVIG
Alive + [23]
9 22 F N.A. His or Cul Liver, stool, urine N.A. Day 19 Noimage
- - Ribavirin Dead - [24]
10 38 M N.A. His or Cul Liver, stool, throat, sputum
N.A. Day113
Noimage
- GradeIII
No specific treatment
Dead + [24]
11 44 F N.A. His or Cul Liver N.A. Day 17 Noimage
N.A. GradeIV
No specific treatment
Dead + [24]
12 24 F ALL Cul Liver, urine, blood, throat
N.A. N.A. Noimage
- - N.A. Dead N.A. [25]
13 44 M CML Cul,PCR,His
Stool, blood, sputum, liver
2 30weeks
Noimage
- + Ribavirin Dead + [26]
14 39 F HD His Liver 2 Day 233
Reported*1
N.A. N.A. DLI Dead N.A. [12]
15 34 M NHL His Liver 5 Day 58 Reported*2
N.A. Grade I N.A. Dead + [13]
16 43 M N.A. His or Cul Liver, stool, throat 2 Day 202
Noimage
N.A. GradeIII
Ribavirin Dead + [27]
17 22 F N.A. His or Cul Liver, stool, urine 2 Day 19 No image
- - Ribavirin Dead - [27]
18 60 M CLL Cul, PCR Intestine, stool, blood 1 Day 148
Noimage
N.A. N.A. Cidofovir Dead N.A. [28]
19 39 M NHL PCR, His
Liver, blood, duodenum, Colon, stool, multiorgan
2 Day 82 Noimage
N.A. - Ribavirin,cidofovir, IVIG
Dead + [29]
20 51 F ALL PCR, His Blood, liver N.A. Day142
Reported*3
N.A. GradeII
Plasma exchange
Dead + [14]
*1 , *2 , *3 : refer to Table2. AML : acute myelocytic leukemia, ALL : acute lymphocytic leukemia, CML : chronic myelogenous leukemia, MDS : myelodysplastic syndrome, HD : Hodgkin’s disease , NHL : Non Hodgkin’s lymphoma, His : histopathology, Cul : culture, PCR : polymerase chain reaction, BAL : bronchoalveolar lavage, IVIG : intravenous immunoglobulin, DLI : donor lymphocyte infusion, N.A.: not available.
Table 2. Images of Adult Allogeneic HSCT Patients with Adenovirus Fulminant Hepatic Failure
No. Age Sex Disease Donor Image Ref
14 39 F HD rBMT Ultrasound and magnetic resonance scans of the liver were abnormal with diffuse non-specific changes.
[12]
15 34 M NHL rBMT Ultrasound scan of the liver showed no focal abnormality. [13]20 51 F ALL uBMT Imaging studies of the liver revealed no apparent space occupying lesion. [14]
The current patient also showed multiple hypoattenuating
lesions mimicking peliosis hepatitis on CT scan. Peliosis
hepatitis is a rare condition characterized by multiple small
blood-filled spaces in the liver parenchyma. CT scan shows
oval-shaped lesions that are homogeneously enhanced after
intravenous injection of contrast agents (19). The liver speci-
men obtained after her death revealed that these lesions cor-
respond to areas of hepatic necrosis, as previously pointed
out in some cases.
We conclude that adenoviral hepatitis should be consid-
ered as a possible cause of liver injury in allogeneic HSCT
recipients with multiple low-density lesions of the liver ob-
served in the CT scan, although such findings are not spe-
cific to adenovirus infection. Accumulation of imaging find-
ings of adenovirus hepatitis is necessary to determine the
characteristic and diagnostic imaging findings of acute or
Intern Med 51: 405-411, 2012 DOI: 10.2169/internalmedicine.51.6432
410
Table 3. Characteristics and Outcomes of Hematological Disorder Patients other than SCT Recipients with Images of Adeno-virus Fulminant Hepatic Failure
No. Age Sex Disease Diagnosticapproach
Diagnosticsites Image Treatment Outcome Other organ
involvement Reference
1 84 y M NHL Histopathology Liver CT : Innumerable small hypoattenuating lesions Cidofovir Died of disseminated
adenoviral infection N.A. [17]
2 4 m F ALL Histopathology LiverUST : Hepatomegaly with multiple intrahepatic microabscesses.
IVIGDied of acute subarachnoidhemorrhage
Colitis [18]
3 2 y M ALL Histopathologyand culture
Stool,throat, and vesicularfluid
UST : Gross hepatomegaly with abnormal heterogeneous echotexture,and ascites.
IVIG, cidofovir and G-CSF
Died of hepatic encephalopathy
Colitis,Skinirritation
[18]
PCR Blood
4 21m M ALL Histopathology Stool UST: Hepatomegaly to the level of the umbilicus.
IVIG and cidofovir
Died of hepatic encephalopathy N.A. [18]
PCR Blood
m : months, y : years, NHL : non-Hodgkin lymphoma, ALL : acute lymphoblastic leukemia, IVIG : intravenous immunoglobulin.
fulminant adenovirus hepatic failure.
The authors state that they have no Conflict of Interest (COI).