CLINICO-PATHOLOGICAL CONFERENCE
Hemophagocytic syndrome associated with fulminant
hepatitis A: a case report
Hiromasa Ishii, Yoshiyuki Yamagishi, Shinichiro Okamoto, Hidetsugu Saito, Haruhito Kikuchi1
and Takahide Kodama2
Departments of Internal Medicine, 1Laboratory Medicine and 2Pathology, School of Medicine
Keio University, Tokyo, Japan(Received for publication on July 10, 2002)

Abstract. A 37-year-old man had a sore throat and pyrexia since January 1999. He was treated at a
nearby hospital, but not improved. Jaundice was indicated there, and the patient was referred transferred to our hospital, where he was admitted for treatment with a diagnosis of severe acute hepatitis
with acute renal failure. Thereafter the patient was revealed to have had a past history of heavy
drinking, and he underwent the treatment with a diagnosis of acute fulminant hepatitis due to hepatitis
A virus (HAV). He showed a tendency toward improvement. During the course, however, viral associated hemophagocytic syndrome (VAHS) developed. Various treatments were conducted, but it was
not improved, and the patient died on Hospital Day 66. On pathologic autopsy, remarkable hepatosplenomegaly associated with marked bone marrow abnormalities compatible with VAHS wasobserved. Aspergillus abscesses were also observed in many organs, and they were considered as anadverse reaction to potent immunosuppressive therapy. Since there have been only a few reports on
HAV-related VAHS, discussing VAHS related to HAV, the present case was considered valuable.
(Keio J Med 52 (1): 38–51, March 2003)
Key words: hepatitis, viral associated hemophagocytic syndrome, fulminant hepatitis, heavy drinking,aspergillosis

whiskey-and-waters 3–4 times a week since he wasabout 30 years old, and gin, vodka, and other alcoholic
beverages, in addition, since he was about 32 years old.
In addition to the daily heavy drinking, he had also
indulged in intemperate and immoderate eating during
the year-end holiday between the end of 1998 to thebeginning of 1999; while also drinking heavily, he had
eaten ﬁsh and shellﬁsh every day during this period. He
developed a febrile sore throat and started to havegastric discomfort from January 4, 1999, and visited
a nearby hospital on January 7. Acetaminophen (amedicine for fever), eprazinone hydrochloride (a coughmedicine) and Ciproﬂoxacin (an antibiotic) were prescribed, and he took the medications for 5 days. At thistime, he had shown transient improvement in responseto the treatment given.
However, on January 21, the patient developed ahigh fever (39.4 C) and arthralgia. He visited another

Doctor Ishii (Moderator): Let me declare the 1051st
clinicopathological conference open.
The patient under discussion today is a 37-year-oldman, whose disease followed a serious clinical course.
The period from the diagnosis of the disease until thetime of death of the patient was approximately only
50 days. He manifested a series of clinical symptoms
during the clinical course, and we had much difﬁculty intreating him.
So, let us start with the case presentation.
Dr. Yamagishi (Internal Medicine): The patient wasa 37-year-old man, whose presenting clinical features
were pyrexia, jaundice and hepatic disorder.
Before I begin with the history of his present illness,
let me mention that he had been documented to havehyperlipidemia several times in company medical
examinations since he was about 28 years old. He wasa habitual alcohol drinker; who had been drinking 6–7

This is a record of the 1051st CPC of Keio University Hospital, held on June 19, 2002.
38

Keio J Med 2003; 52 (1): 38–51

nearby hospital on January 22. He was diagnosed tohave an upper respiratory tract infection caused by theinﬂuenza virus, and an antibiotic was administeredintravenously by drip infusion. Concomitantly, he also
received the following medication: cefdinir (an antibiotic), diclofenac sodium (an antipyretic), ambroxolhydrochloride, teprenone, domperidone, an expectorant. His symptoms however, did not resolve. He
reported passing high-colored urine from January 23,
and developed anorexia and general fatigue on January
25.
On the following day, on January 26, he found it
difﬁcult to even drink water and could not take any oral
medication. He developed right hypochondrial pain,
and frequent vomiting and diarrhea, and again visitedthe nearby hospital. Hematological examination at thattime revealed marked liver dysfunction, with a serum
GOT of 14,500 IU/L and serum GPT of 10,800 IU/L.
The patient was therefore referred to Kitasato InstituteHospital. From there, with the suspected diagnosis ofsevere acute hepatitis, he was transferred to our hospital and admitted to the GICU ward.
His past history was unremarkable, except for thefrequent documentation of hyperlipidemia in company
health examinations. There was no history of bloodtransfusion.
The patient was a heavy alcohol drinker, and had along history of having a few glasses to half a bottle of
low-class distilled spirits daily. As mentioned above, he
had been drinking rather heavily since he was about
30 years old. He also smoked about 20 cigarettes a day.
In regard to his occupational history, he edited video
ﬁlms for a TV channel. There was no history of allergy.
In the family history, the patient’s father had gastriccancer and gallstones.
Dr. Ishii: Thank you, Dr. Yamagishi. We just heard
from Dr. Yamagishi the chief complaints, history ofpresent illness, past history, personal history and family
history of today’s patient. In brief, the patient was a37-year-old man who was a habitual very heavy alcohol
drinker. He gave a history of intemperate eating anddrinking every day during the New Year’s holiday between the end of 1998 and the beginning of 1999. In theﬁrst week of January 1999, he developed gastric discomfort and other symptoms, and had received medication from a local hospital, with some transient improvement. As may be expected, the quantity of alcohol
consumed had reduced during this period, but he still
continued to drink. About 2 weeks later, he developed
a high fever (39.4 C), and received treatment for a suspected diagnosis of inﬂuenza virus infection from another local hospital.
Dr. Yamagishi, what exactly was the drug administered by intravenous drip infusion at this time, andwhat exactly were the other medications administered39

on this occasion? Antibiotics and what internal medicines?
Dr. Yamagishi: They were antibiotics, and nonsteroidal anti-inﬂammatory drugs (NSAIDs). A medicine for the stomach discomfort was also used.
Dr. Ishii: And the symptoms did not resolve withthis treatment. On the contrary, the patient developed
anorexia, dizziness, nausea, diarrhea, and high-coloredurine despite the treatment. Was that the reason thepatient visited the same hospital again?
Dr. Yamagishi: Yes. He visited this hospital on January 21 and 26. On January 7, however, he had visitedanother hospital.
Dr. Ishii: We were surprised indeed to hear thatthe laboratory examination revealed a GOT of 14,500
IU/L and a GPT of 10,800 IU/L. Does anybody haveanything more to ask until this point in the course of thepatient’s illness?
Mr. Igarashi (6th-year student): This patient wasreferred to our hospital on January 26? Had he been
detected to have hepatic dysfunction on earlier healthexamination or other examinations?
Dr. Yamagishi: No, serum aminotransferases (GOTand GPT) had been normal earlier.
Mr. Izumi (6th-year student): The patient had frequent vomiting and diarrhea according to the report.
Could we have some more information regarding thecolor and other characteristics of the stools?
Dr. Yamagishi: No speciﬁc ﬁndings had beenrecorded before admission, but after admission, hisrecords show that he passed white stools.
Dr. Ishii: Did he ever have bloody stools?
Dr. Yamagishi: No, he never had either bloody stools
or tarry stools.
Mr. Izawa (6th-year student): With regard to theright hypochondrial pain, had he ever had similar pain
before? Also, could you let us know if the hypochondrial pain was persistent or intermittent, and colicky or
dull.
Dr. Yamagishi: No, he had never had such pain
before. When he was examined at our hospital, severe
right hypochondrial tenderness was noted. His pain wasdull, although he reported intermittent increase in its
severity.
Dr. Ishii: Mr. Izawa, yes, it is very important to know
about the characteristics of the pain. It is a good question, but may I ask exactly why you enquired about thecharacteristics of the pain?
Mr. Izawa: This patient had been documented tohave hyperlipidemia, which is known to be a risk factor
for cholesterol calculi in the gall bladder. So, if this patient had intermittent and colicky right hypochondrial
pain, the possibility of cholelithiasis and/or cholecystitis
may also have to be considered.
Dr. Ishii: This patient had pyrexia and hyper-

40Ishii H, et al: Acute viral hepatitis A and hemophagocytic syndrome

lipidemia, and was a heavy alcohol drinker. Anyhow,
your question was based on the possibility of acutecholecystitis occurring in this patient; good. On laboratory examination, the GOT and GPT levels exceeded
10,000 IU/L. Is it not odd? Fulminant hepatic necrosis
may have been present. Do you have anything to addon that, Dr. Yamagishi?
Dr. Yamagishi: Even at the ﬁrst hospital that thepatient had visited, the serum lactate dehydrogenase(LDH) level had been documented to be markedly
elevated to 14,900 IU/L. The total bilirubin level had
also been determined at Kitasato Institute Hospital; it
was very high – the value was 8.25 mg/dl.
Dr. Ishii: On January 26, the patient developed difﬁculty in even drinking water, and the next day, he wasreferred to Kitasato Institute Hospital. GOT and GPT
are the so-called aminotransferases; when hepatocytes
are disrupted, these enzymes leak into the peripheral
blood. Mr. Izawa, if we were also to consider the diagnosis of gallstones/cholecystitis at this point, could wehave some additional information on other liver function test results as well?
Mr. Izawa: May I ask for the serum levels of alkaline
phosphatase (ALP), leucine aminopeptidase (LAP)
and g-glutamyl transpeptidase (g-GTP)?
Dr. Yamagishi: The g-GTP level had been determined at the ﬁrst hospital, and it was 269 IU/L. Thislevel was high, although less markedly so than the serum GOT and GPT. The ALP level was not measured
at the ﬁrst hospital. There was no documentation of theg-GTP or ALP level at the Kitasato Institute Hospital.
The serum LAP had not been measured at either theﬁrst hospital or at the Kitasato Institute Hospital.
Dr. Ishii: At present, ALP, g-GTP and LAP are frequently used as markers of disease of the biliary system. Each of these enzymes reﬂects one aspect of thefunctions of the biliary system, and all are important
enzyme markers. Their levels were elevated in this patient, but the elevations were less marked than the abnormal elevations of the serum GOT, GPT and LDH,
which are reﬂective of disorders of the hepatocytes
themselves, right?
Dr. Yamagishi: That’s right.
Dr. Ishii: That is the reason why the patient was admitted to our Keio University Hospital. Dr. Yamagishi,
could you please show us the ﬁndings on physical examination and the laboratory test results of this patientat admission to our hospital?
Dr. Yamagishi: The patient was slightly obese. The
blood pressure was 131/76 mmHg, pulse rate was 93/
min and regular, and the body temperature was 38.0 C.
There was no anemia, but severe icterus was noted.
Xanthoderma was also noted. There were no abnormal
ﬁndings on examination of the oral cavity. Struma was
not present, and there was no cervical lymphadeno-

Table 1

Laboratory Data

WBC
Band
Seg
Lym
Alym
Mono
Hb
Plt
Ret

16200/ml
16.0%
50.0%
23.0%
3.0%
8.0%
13.8 g/dl
140000/ml
30

PT
APTT
FNG
FDP
D-dimer

21%40.8 sec
144 mg/dl
1497 ng/dl
80.6 mg/ml

TP
ALB
ZTT
TTT
TB
DB
LDH
GOT
GPT
GGTP
ALP
ChE
BUN
CRTNN
UA
NH3
CRP

6.3 g/dl
3.2 g/dl
13.6 KU
7.5 KU
7.3 mg/dl
6.3 mg/dl
1640 IU/l4130 IU/l5780 IU/l
337 IU/l
896 IU/l
198 IU/l
42.7 mg/dl
9.1 mg/dl
16.5 mg/dl
42 mmol/ l
3.77 mg/dl

HA-IgM Ab
HBs AgHBs AbHBe AgHBe AbHBc AbHBV DNAHCV Ab
HCV-RNA
CMV-IgG
CMV-IgM
EB-IgG
EB-IgMEBNA
HIV AbHPVB19-IgG
HPVB19-IgM
ANA

(þ)
()
(þ)
()
()
(þ)
()
()
()
(þ)
()
(þ)
()
40
()
(þ)
()
()

pathy. No abnormal ﬁndings were noted on cardiopulmonary examination. The abdomen was soft andﬂat. The liver was palpable 2 ﬁngerbreadths below theright costal margin, and was soft to elastic in consistency; it was tender to palpation. The spleen was not
palpable. There was no pedal edema. The patient was
fully conscious and alert, and there was no consciousness disturbance. Flapping tremor was absent. No
abnormalities were found on neurological examination.
As for the results of the laboratory tests undertaken
at admission (Table 1), the erythrocyte sedimentation
rate was 7 mm/h, and the white blood cell count (WBC)was markedly elevated to 16,200/mL. The hemoglobin(Hb) was 13.1 g/dl, the platelet (PLT) count was
140,000/mL, and the reticulocyte (Ret) was 3‰. In the
coagulation proﬁle, the prothrombin time (PT) was
21.0%, markedly prolonged. The ﬁbrinogen was 144
mg/ml, which was within normal range, and the ﬁbrindegradation products (FDP) level was markedly elevated to 1497 ng/ml.
Dr. Ishii: OK, then, let’s go back slightly. Could you
please go over the patient’s history once more for recapitulation?
Dr. Yamagishi: The patient was a heavy drinker andhad been drinking alcohol since he was about 20 years
old. He had a few glasses to half a bottle of low-classdistilled spirits at least 3–4 times a week. Since he wasabout 30 years old, he also had whiskey-and-water frequently. Since the age of 32 years, he had had half abottle of gin, vodka, or other such drinks almost everyday. He was an editor of video ﬁlms, and was single. He
often drank while doing his editing work at night. He
had led his life without differentiating night from day.
He smoked 20 cigarettes a day. Particularly during theholiday period between the end of 1998 and the begin-Keio J Med 2003; 52 (1): 38–51

ning of 1999, he had drank and eaten without moderation every day, both at parties and while working.
Dr. Ishii: His drinking habit is a very important partof the patient’s history, isn’t it? Our patient was a heavy
drinker, and perhaps also a habitual smoker, sinceaccording to the history, he smoked about 20 cigarettes
a day, right? He also ate and drank immoderately andintemperately during the year-end holiday between
1998 and 1999, until a few days before and even after
the onset of his symptoms. He had had raw ﬁsh anduncooked seafood often during this period, right?
We have so far heard about the erythrocyte sedimentation rate, peripheral blood ﬁndings and the coagulation proﬁle at the time of his admission. Will you
now please also tell us the other biochemical test resultson admission?
Dr. Yamagishi: Yes, the serum TP was 6.3 g/dl and
ALB was 3.2 g/dl; both were slightly decreased. Remarkably, the serum TB was elevated to 7.3 mg/dl; direct bilirubin level (DB) was predominant, at 6.3 mg/dl.
The BUN was 42.7 mg/dl, CRTNN was 9.1 mg/dl, andUA was 16.5 mg/dl. Thus, there was also marked renal
dysfunction. In regard to the electrolyte levels, theserum Na was normal, but the serum K was elevated to
6.0 mEq/L. The increased potassium level may havebeen associated with the renal failure.
Furthermore, the serum LDH was elevated to 1,640
IU/L. As to the subfractions, fractions L3, L4 and L5
were signiﬁcantly elevated. The serum GOT was 4,130
IU/L, GPT was 5,780 IU/L, ALP was 896 IU/L, and
LAP was 218 IU/L. While the latter levels seemed
to have improved slightly as compared to the levels
recorded at the earlier hospitals, the GOT and GPT
were still markedly elevated. The serum g-GPT and
creatine phosphokinase (CPK) were elevated to 337
IU/L and 1,332 IU/L, respectively. There was no documentation at our hospital, but the serum CPK-MB, thefraction derived from the heart, was not elevated.
On admission, the NH3 level had decreased to 42
mmol/L from the level of 93 mmol/L recorded at theKitasato Institute Hospital. The serum IgG and IgMlevels were elevated to 2,050 mg/dl and 477 mg/dl, respectively.
The serum marker proﬁle of vital hepatitis was asfollows: positive for HA-IgMAb, negative for HBsAg,
positive for HBsAb, negative for HBeAg, negative for
HBeAb, and positive for HBcAb. The patient was
negative for HBc (200%). He was also negative for
HBc-IgMAb, HBV-DNA, and for both the antibody to
and RNA of HCV.
Dr. Ishii: Mr. Izumi, would you have any commentson the data that we have just heard?
Mr. Izumi: Some diseases of the liver may be suspected from the biochemical data. The serological dataalso indicate that there was probably no active hepatitis

41

B or C infection. Hepatitis A virus (HAV)-IgM was
positive, suggesting that the patient probably had active
hepatitis A virus infection.
Dr. Ishii: Do you think the liver function abnormalities were related to the HAV infection?
Mr. Izawa: Taking into consideration the serologicalﬁndings, it is highly likely that the patient had acuteviral hepatitis A. However, if only the biochemicalﬁndings were considered without taking into consideration the serological data, the elevation of CPK without
elevation of the MB isotype suggests that the ﬁndings
may have been due to the habitual heavy alcohol consumption. There was also renal failure as indicated by
the elevated levels of BUN, CRTNN, and K, and when
all the ﬁndings are considered comprehensively, hepatic
disorder due to gallstones and/or cholecystitis may also
be considered, as mentioned previously. Other possibilities, i.e., disorders of the biliary tract associated withsecondary renal dysfunction may also have to be considered.
Dr. Ishii: So, gallstones/cholecystitis, and renal failure secondary to gallstones/cholecystitis, and alcoholrelated disorders may have been related to his condition. Is that right?
Mr. Izawa: The serum CPK level was increased ﬁrst.
It was too high to become a reference, but the GOT
was also elevated. High levels of enzymes related tothe biliary tract, including ALP, LAP and g-GTP, werealso present. Could you also please let us know theserum triglyceride level, which was not mentioned withthe ﬁndings?
Dr. Ishii: Yes, the serum triglyceride level. . . .
Dr. Yamagishi: Tryglyceride was not measured on
admission. When hyperlipidemia was documented during his earlier medical examinations, the serum totalcholesterol was approximately 250 mg/dl. At this time,
the serum triglyceride level was approximately 400 or
500 mg/dl. Thus, it may be assumed that the serum triglyceride level was also high on admission.
Dr. Ishii: The serum cholesterol was approximately
250 mg/dl, and the triglyceride was 400–500 mg/dl orover. The normal level of triglyceride ranges from 70–
80 to approximately 150 mg/dl. Heavy drinkers often
have levels in the range of 300 to 500 mg/dl. A very
important morbid condition may be considered fromthe relationship of CPK to alcohol, in the presence ofrenal failure. CPK is an enzyme that is present abundantly in the muscle. Elevation of this enzyme levelmay suggest that disruption of muscle, particularly striated muscle, that has caused leakage of the enzyme into
the peripheral blood. So, in heavy drinkers, what do
you think has happened when the serum CPK level iselevated?
Mr. Izawa: Myositis may be caused by alcohol consumption. The associated rhabdomyolysis induces re-42Ishii H, et al: Acute viral hepatitis A and hemophagocytic syndromelease of the MB fraction of CPK, which causes proximal
tubular dysfunction in the kidney. That could have
happened.
Dr. Ishii: I see. Rhabdomyolysis is sometimes associated with alcoholism. Particularly, it occurs in alcoholics, often causing renal failure. Oliguria and anuria
may also occur. In some cases, the serum CPK levelmay be elevated from 1,000 to 2,000 or 3,000 IU/L. Thismorbid condition is very uncommon, but as Mr. Izawa
thinks, it must be kept at the back of the mind for thetime being.
Mr. Ikegami (6th-year student): I also think that theinﬂuence of alcohol should never be ignored. Hepatitis
A is the most plausible diagnosis based on the serological test ﬁndings. In particular, at least the other viral
hepatitis can be ruled out from the serological ﬁndings.
In cases of hepatitis with elevated serum CRP level,
hepatitis A would be suspected ﬁrst among the viral
hepatitis. The levels in the present patient were characteristic of hepatitis A; thus, hepatitis A would be themost plausible diagnosis.
Dr. Ishii: Yes, you have a very good point. Hepatitis
with elevated serum CRP level is most frequently seen
in cases of hepatitis A.
Can you tell us what other possible diseases should
be kept in mind, Mr. Igarashi?
Mr. Igarashi: The count of atypical lymphocytes in
the peripheral blood was 3%, suggesting that infectious
mononucleosis is a possibility. However, in this patient,
this is unlikely because of the absence of peripheral
lymphadenopathy. Still, hepatic dysfunction was associated with hepatosplenomegaly, in addition to lymphocytosis; therefore, infectious mononucleosis may
have to be considered as a possibility.
Dr. Ishii: Infectious mononucleosis? The patient did
not have lymphadenopathy – so what do you think ofthat?
Dr. Yamagishi: No, the patient did not have lymphadenopathy.
Dr. Ishii: Lymphadenopathy is an important ﬁnding.
Although it is possible to ﬁnd that in physical examination, CT or ultrasonography of the abdomen may reveal
enlarged para-aortic lymph nodes. Therefore, it should
be considered as one of the possible diagnoses.
Mr. Abe, do you have any comments?
Mr. Abe (6th-year student): Various medicines had
been prescribed to the patient for the treatment of coldlike symptoms. Therefore, drug-induced hepatitis may
also have to be considered.
Dr. Ishii: Right. During the 2–3 weeks between early
January and January 27, various medicines had been
administered to the patient. Thus, drug-induced liverdisease may indeed have to be considered as a possibility. Do you have any comments about other possible
morbid conditions?

Mr. Izumi: I have a question. Was the patient’s fundus examined at admission for papilledema?
Dr. Yamagishi: Papilledema was not examined.
Mr. Izumi: If we consider infectious mononucleosis
as a possibility as mentioned earlier, what were the antibody titers to Epstein-Barr (EB) virus in the serum?
What other tests were performed to substantiate or ruleout the diagnosis? Could you please let us know?
Dr. Ishii: Dr. Kikuchi of the Department of Laboratory Medicine, would you please answer that question?
Dr. Kikuchi (Department of Laboratory Medicine):
EBV antibody-IgG and antibody-IgM examined in thispatient were the antibodies response to the various
antigens of EB virus. They are not antibodies to speciﬁc
antigens of EBV, such as viral capsid antigen (VCA),
early antigen (EA) and Epstein-Barr virus nuclear antigen (EBNA). Basically, in EBV infection disease, IgM
is elevated in the initial stages, and later, IgG, is elevated. When the latter alone is elevated, it indicatesmainly past infection. In the present patient, EBNA
was examined separately. EBV-IgG and -IgM antibodies, which are the tests performed generally at our
hospital at present, are not antibodies against speciﬁc
EBV antigens as I just commented.
Mr. Izumi: Autoimmune hepatitis should also be
considered in the differential diagnosis.
Dr. Ishii: Why do you think so?
Mr. Izumi: There is no speciﬁc evidence, but I
thought it may be necessary to consider autoimmune
hepatitis, because the patient after all had hepatitis.
Dr. Ishii: Before considering autoimmune hepatitis,
let us discuss the immunoglobulins levels in the patient,
as it is a very important issue. In this case, the overall Ig
level, including IgG, IgA and IgM, was found to be approximately 2,800 mg/dl on admission. Thus, there wasprobably a polyclonal elevation of the g-globulin level.
The test for antinuclear antibody was negative, whichgoes against the consideration of autoimmune hepatitis,
nevertheless, this condition may have to be kept inmind as a differential diagnosis.
Bone marrow aspiration was performed in this patient at admission, wasn’t it? Would you please tell us
about that? Also, let us see the ﬁndings of CT and otherimaging studies.
Dr. Yamagishi: Because of marked renal dysfunction, contrast-enhanced CT was not performed.
Dr. Ishii: Iodine was probably not used because of
the presence of renal failure?
Dr. Yamagishi: That’s correct. The liver was swollen
with tension, showing a considerably lower density ascompared to the spleen. The spleen was also swollen.
There was no ascites. Severe renal dysfunction waspresent on laboratory data, but no renal atrophy wasobserved.

Keio J Med 2003; 52 (1): 38–51

Fig. 143

Outline of the clinical coarse. PE: plasma exchange, HDF: hemodiaﬁltration.

Dr. Ishii: Dr. Yamagishi said now that the liver
showed uniformly low density, but how do you see this?
The density must be seen in contrast with anotherorgan. Certainly the liver is low density in this case. It is
important to compare its density with the density ofnormal liver. Usually, the spleen and the liver show
isodensity. In this case, the liver is distinctly of lower
density than that of the spleen. In addition, the liver
showed diffusely low density.
When low density is diffusely present as comparedto the density of the spleen, what should be considered ﬁrst, I wonder. If a local space-occupying lesionshows low density, various possibilities can be considered. In the case of diffuse low density, however, themost important condition that must be considered is alcoholic liver disease. Fatty liver may also be considered,
which is also commonly seen in alcohol liver disease. The
diffuse low density is caused by fatty inﬁltration.
Signiﬁcant swelling of the liver and low density arecharacteristic of a fatty liver.
Dr. Yamagishi: This is a supplementary ﬁnding,but the gallbladder is also considerably contracted, withthickening of the wall.
Dr. Ishii: The gallbladder can be visualized andshows generalized contraction. The gallbladder isknown to contract after meals. So, how would one
judge the contraction in this case, Dr. Yamagishi?

Dr. Yamagishi: A contracted gallbladder with thickening of the wall is quite frequently seen in acute phaseof severe hepatic disorders.
Let me now describe to you the course of the patient
after admission (Fig. 1). The patient was diagnosed
to have severe acute hepatitis at the Kitasato InstituteHospital, and acute renal failure was diagnosed to bepresent, in addition, at our hospital. From the day ofadmission, marked prolongation of PT was observed.
Administration of FFP was started for supplementationof coagulation factors, and hemodialysis was started for
acute renal failure. Steroid pulse therapy was started
with 500 mg of methylprednisolone (mPSL) for thetreatment of the liver disorder. On the day after admission, the patient developed Grade II hepatic encephalopathy with ﬂapping tremor. At this point, he wasdiagnosed to have acute fulminant hepatitis according
to the diagnostic criteria established at the Inuyama
Symposium, and plasma exchange (PE) and hemodiaﬁltration (HDF) were started.
On hospital day 6, the serum GOT and GPT levels
and the PT showed marked improvement to 63 IU/L,
348 IU/L and 71%, respectively, in response presumably to the steroid administration, PE and HDF. The
encephalopathy improved and the PE and HDF were
stopped. However, hemodialysis was continued for the
renal dysfunction. For 3–4 days after admission, the44Ishii H, et al: Acute viral hepatitis A and hemophagocytic syndrome

patient had anuria, but thereafter diuresis occurred, andthe renal function also tended to gradually improve.
While the dose of the steroid was being tapered, however, the patient developed some other symptoms; from
hospital day 18, when the dose of PSL was tapered to
20 mg, pyrexia of over 39.00 C, marked elevation of
the serum CRP, and thrombocytopenia developed, and
the PLT count decreased to under 10,000/mL, despite
PLT transfusion every day. On hospital day 24, bonemarrow aspiration was done. This revealed numerous
activated macrophages with phagocytosed hemocyteswith vacuoles. Taking into consideration this ﬁnding
along with the clinical course, the patient was diagnosed
to have hemophagocytic syndrome (HPS).
From hospital day 28, steroid pulse therapy with1,000 mg mPSL and administration of gabexate mesilate (FOY) were started. With this treatment, the pyrexia tended to resolve, the temperature reduced to
37.00–38.00 C, the serum CRP level decreased slightly.
A bone marrow aspiration has done again on hospital day 36, however, still revealed macrophages withphagocytosed activated hemocytes. In consultation withhematological physician, chemotherapy with Cyclophosphamide, Vincristine, and Prednisolone (COP
therapy) was started from hospital day 36.
Subsequently, the PLT count improved to over
30,000/mL, and the frequency of PLT transfusions could
be reduced. The total bilirubin, which had risen to
40 mg/dl, decreased to under 30 mg/dl. However, granulocytopenia, which may be considered to be a side
effect of chemotherapy, developed, and this could becorrected to some extent by the administration of GCSF. The general condition of the patient seemed toshow some gradual improvement, but on hospital day
48, the patient developed a cerebral hemorrhage, andwent into respiratory arrest. Mechanical ventilation was
initiated, and glyceol was administered for cerebral
edema. However, the patient did not respond to thetreatment, and died on hospital day 66.
Dr. Ishii: We just heard the patient’s clinical course
after his admission to the hospital until his death. After
admission, various examinations were conducted. It wasstated that while tests were being performed to conﬁrm
the diagnosis, the patient developed acute fulminant
hepatitis. You students also often use the term ‘‘fulminant hepatitis’’, but what is acute fulminant hepatitis? Mr. Izumi, what are your comments on the diagnosis of acute fulminant hepatitis?
Mr. Izumi: The criteria established at the Inuyama
Symposium include the following in the category ofhepatitis: fulminant hepatitis is characterized by having
Grade II or more severe encephalopathy and severe
liver dysfunction occurring within 8 weeks of the appearance of symptoms, with a prothrombin time of 40%
or less. On the basis of these criteria, this patient’s

condition could be diagnosed as fulminant hepatitis.
Within 10 days of the appearance of symptoms, encephalopathy occurred, reﬂecting the acuteness of thecondition. Thus, the patient was diagnosed to haveacute type fulminant hepatitis.
Dr. Ishii: I see. Dr. Saito, could you comment on the
diagnosis of fulminant hepatitis in this case?
Dr. Saito: The diagnostic criteria for fulminant hepatitis which were just mentioned by student Izumi arecorrect; they were established at the Inuyama Symposium. But I must say that the categorization of acutehepatic failure is somehow different between Japan andother countries. Therefore, I am going to talk about
the Japanese consensus of fulminant hepatic failure.
Fulminant hepatitis is included as a category of acutehepatic failure, in which the function of the liver as anorgan becomes severely impaired because of rapid disruption of a large number of hepatocytes. There are
acute and subacute types of fulminant hepatitis; in theacute type, disturbance of consciousness appears within
10 days of the onset of symptoms, and in the subacute
type, disturbance of consciousness develops on or after
the 11th day of the occurrence of symptoms. In general,
the subacute type is more severe. The life of a patientwith the subacute type can rarely be saved; the survival
rate in cases with the acute type is approximately 50–
60% and that of cases with the subacute type is currently estimated to be 30% (20% according to previousdata). Acute hepatic failure is also not infrequently
associated with hepatitis A.
Dr. Ishii: Thank you, Dr. Saito.
Then, we would like to ask Dr. Yamagishi, the physician-in-charge of the patient, about the survival rateof cases of acute fulminant hepatitis, the eventual diagnosis in this patient, and the treatment for the condition.
Dr. Yamagishi: There was clear evidence that thepatient had acute hepatitis A. Even in cases with acutehepatitis A, elevation of the GOT and GPT to over
10,000 IU/L is not considered to be common. The
heavy alcohol consumption was considered to have hadmuch inﬂuence on the clinical condition and laboratory
abnormalities in the present case.
With regard to renal failure, nephropathy is wellknown to be associated with severe acute hepatitis A.
Although the cause still remains unknown, many cases
develop acute tubular necrosis. There is a hypothesisthat immune complexes precipitate in the kidney tolead to renal failure. Other factors, including the inﬂuence of alcohol or drugs, because antipyretics, particularly NSAIDs, and antibiotics, had been used in highdoses, may also have been related to the developmentof renal dysfunction in this patient.
In other words, acute hepatitis A was present as theunderlying disease, and the condition became severeKeio J Med 2003; 52 (1): 38–51

due to the additional inﬂuence of alcohol in this case.
Drugs also probably inﬂuenced the underlying disease.
The condition in the patient worsened, with the development of fulminant hepatitis, encephalopathy and renal failure in this patient.
Dr. Ishii: We understand that acute hepatitis A wasdiagnosed based on the clinical ﬁndings, but there isanother problem. We must also consider the possibilityof a very important complication or disease secondary
to the hepatitis, based on the manifestation of marked
pyrexia and the changes in the hemopoietic system.
In particular, marked thrombocytopenia started to be
seen from hospital day 18 (middle of February). Sucha complication in association with hepatitis A is extremely rare. So, what was the cause of this? We presented the various hematological ﬁndings and discussed
the case with Dr. Okamoto. We asked him that under
the circumstances, what had actually occurred in thispatient? The data will be discussed by Dr. Okamoto,but before that, Dr. Yamagishi, will you please tell us
about the bone marrow aspiration?
Dr. Yamagishi: Thrombocytopenia was marked andthe PLT count did not increase despite PLT transfusion every day. In order to determine the cause of thedecreased PLT count and the treatment strategy, we
consulted with hematological physician at our hospital,and decided to perform a bone marrow aspiration.
Dr. Ishii: Dr. Okamoto, will you please explain thecondition of the patient, as well as the results of thebone marrow aspiration?
Dr. Okamoto (Internal Medicine): When we saw thispatient with severe thrombocytopenia, we assessed
whether the patient had depressed hemopoiesis, orconditions in which blood cells were rapidly consumed
or destroyed. The ﬁndings of severe thrombocytopenia
outpropotional to anemia and leukopenia, a shift ofgranulocytes to the left, and increased RET counts
support the latter possibility. Bone marrow biopsy was
performed to conﬁrm this, and revealed hypercellularmarrow with marked hemophagocytosis (Fig. 2).
I will ﬁrst give a general overview of the condition
called HPS (hemophagocytic syndrome), and then discuss the possible causes of HPS in this patient.
This slide shows bone a marrow smear of thispatient. Bone marrow is normocellular with normal
erythroid and myeloid differentiations. A macrophage
is observed in the center, and you can see the macrophage eating and digesting red cells and platelets(Fig. 3).
This is a bone marrow smear of another patient withlymphoma. This patient also had severe HPS. You
can see platelets, granulocytes, and erythroblast being
phagocytosed and digested by a macrophage.
When a bone marrow smear is prepared, macrophages and RBCs may overlap each other, and occa-

45

Fig. 2 Bone marrow macrophage from this patient. The macrophageshows platelet phagocytosis.

Fig. 3 Bone marrow macrophages from a patient with lymphoma.
These macrophages show platelet phagocytosis, band neutrophil anderythro-phagocytosis.

sionally result in an image like phagocytosis. However,
if you check smears carefully, you can see the clear
zone around phagocytosed cells in the cytoplasm. Thisis a typical ﬁnding of endocytosis.
HPS is a clinical entity characterized by activationand proliferation of histiocytes and macrophages. As
a result, mature blood cells are phagocytosed anddigested by these activated cells in the bone marrow.
Phagocytosis does not necessarily occur only in thebone marrow; it may also occur in the liver and thespleen. In order to diagnose this syndrome bone marrow aspiration is the most valuable tool. If phagocytosis
in the bone marrow is not distinct, the liver and thespleen may also be biopsied, but the yields are comparatively low.
Clinical features of HPS are largely attributable tothe cytokine storm, i.e., a condition in which a large
amount of cytokines is produced. It has been believed

46

Ishii H, et al: Acute viral hepatitis A and hemophagocytic syndrome

Table 2 Classiﬁcation of Hemophagocytic Syndrome in Adults(N ¼ 52)
Underlying disease
Lymphoma-associated hemophagocytic syndrome(LAHS)
T/natural killer lymphoma
B lymphoma
T/B unknown
Virus-associated hemophagocytic syndrome (VAHS)
Epstein-Barr virus
Measles
Parainﬂuenza
Hepatitis A
Not identiﬁed
Bacteria-associated hemophagocytic syndrome(BAHS) and fungal infections
Mycobacterium tuberculosis infection
Staphylococcus aureus infection
Pseudomonas aeruginosa infection
Corynebacteria infection
Candida albicans infection
Autoimmune-associated hemophagocytic syndrome(AAHS)
Systemic lupus erythematosus

No. of cases

12
12
2
4
1
1
1
10

2
1
1
1
1

3

(Reproduce from Takahashi N, et al: Int J Hematol 2001; 74: 209–213,
Copyright : (2001), with permission from The Japanese Society of
Hematology)

that macrophages and histiocytes are activated by the‘‘cytokine storm’’ in this condition. The clinical ﬁndings
include high fever, hepatomegaly, splenomegaly, cytopenia due to phagocytosis of blood cells. Laboratory
ﬁndings showed elevation of LDH due to destruction ofblood cells and high level of CRP, soluble-interleukin-2
receptor (sIL)-2R, triglyceride and ferritin, which are
attributable to the increased cytokine levels. Liver dysfunction and abnormal coagulation proﬁles are also
observed (Table 2).
What are the underlying diseases associated with
HPS? As mentioned by Prof. Ishii, HPS is rarely associated with hepatitis A, according to a nationwide survey of HPS in adults by Akita University School of
Medicine. The most common underlying disease associated with HPS was lymphoma, followed by viral
infections (so-called virus-associated hemophagocytic
syndrome; VAHS). It has been reported that VAHS
may be associated with EB virus, measles, parainﬂuenza, hepatitis A, parvovirus, herpes simplex virus,
herpes zoster virus and adenovirus infections. Ten cases
associated with possible viral infection, in which causative viruses could not be identiﬁed, have beenreported. Severe bacterial infection or fungal infection,
just like viral infection, have also been reported to be
associated with HPS. Similarly, HPS has also beenreported in association with severe autoimmune diseases.

Fig. 4 Schematic representation of the cytolytic effector cell defectin HLH. (Reproduce from Arico M, et al: Br J Hematol 2001; 114:
761–769, Copyright : (2002), requesting permission from Blackwell
Publishing)

On the other hand, many familial cases have beenreported in children. That is called familial hemophagocytic lymphohistiocytosis (FHL). The incidence of
HPS related to EBV virus infection seems to be higher
in children (Fig. 4).
This is my last slide, showing the mechanism ofhemophagocytic lymphohistiocytosis in children. Hereyou can see a virus-infected cell, and cytotoxic T lymphocyte (CTL), natural killer (NK) cell attacking theinfected cell. When NK cells attack infected cells, theyoften secrete perforin to make holes at the cell surface,
and inject a substance called granzyme into the holes,
which induces apoptosis of the cell. In pediatric patientswith FHL, the ability of NK cells to produce perforin ismarkedly decreased or deﬁcient. Therefore, while NK
cells are activated, infected cells are not killed. As aresult, cytokines are constantly produced and macrophages continue to be activated, and result in HPS.
Therefore, not macrophages (MP), but NK cells and T
cells are responsible for the occurrence of HPS. In
lymphoma, there is a possibility that lymphoma cells
themselves also produce cytokines.
In this patient, NK cells or CTL had some defects,
and the infected cells could not be killed because of thehealing process, as a result, the ‘‘cytokine storm’’ may
have progressed. It is also possible that T cells or NK
cells show clonal proliferation in this condition, while
the infection settled. The possibility of another viral
infection, not hepatitis A, having occurred during thehealing process of hepatitis A cannot be ruled out. Thisviral infection may have been the cause of HPS in thispatient.
As for the treatment of HPS, it is most importantto suppress the ‘‘cytokine storm’’. Steroids and cyclosporine should be administered to suppress cytokine
production from T cells and/or NK cells. When these
therapeutic procedures fail, hemopoietic stem cell

Keio J Med 2003; 52 (1): 38–51

transplantation may be considered to eliminate theproliferating T cells or NK cells completely. There havebeen a limited number of reports of stem cell transplantation in HPS. Liver transplantation has also been
performed, in addition to hemopoietic stem cell transplantation in some patients.
In conclusion, hepatitis A may have triggered the
HPS in this patient, and subsequently the ‘‘cytokine
storm’’ persisted, and contributed to the fatal course.
What I want to know is whether another infection suchas EBV infection was present, whether the hepatitis A
infection was completely resolved at the time of occurrence of HPS, and ﬁnally, whether the HPS in thispatient was associated with lymphoma, although this isunlikely.
Dr. Ishii: We understand that very well; any questions?
Mr. Tamura (5th-year student): A doctor mentioned
previously that it was difﬁcult to make a diagnosis basedon a correlation among hepatitis, the patient’s symptoms, and the laboratory test values. In this patient,the ferritin level was considered to be very abnormal.
While the accurate condition was not known because
the RBC count was not monitored, in general, the ferritin level seemed to be elevated. What are the possible
reasons for elevation of the ferritin levels in cases ofhepatitis?
Dr. Saito: Usually, the ferritin level is not elevated incases of viral hepatitis. In cases of liver transplantation, that are always due to chronic and acute liver diseases in adult, VAHS or hemophagocytosis happens to
be complicated. If the activity of VAHS or hemophagocytosis is severe, the prognosis of the patient will be
determined by the severity of the hematological diseases, even if the liver is successfully transplanted. We
must decide whether or not the transplantation shouldbe performed. In such cases, the phagocytotic activity
may be judged from serum level of ferritin and IL-2R.
Mr. Tamura: In the familial type mentioned previously, it was said that the condition is caused byweakening of the functions of CTLs and so on, right?
Then, is this not manifested by any other signs, such asincreased susceptibility to infections from birth?
Dr. Okamoto: It’s a good question. Pediatric patientswith FHL do not often live to grow into adults. So, inmost adult patients, HPS is associated with lymphoma
or viral infection. However, HPS in association with
hepatitis A is rare, even though the hepatitis is severe.
It is plausible to speculate that abnormalities in the immune system, which are being increasingly clariﬁed inpediatric patients, may also exist in adults. But this is a
speculation, and has not been demonstrated.
Mr. Izumi: This patient had acute fulminant hepatitis
and should have had a better prognosis than cases withsubacute fulminant hepatitis. Did you consider liver

47

transplantation in this patient?
Dr. Ishii: Yes, I was going to ask Dr. Saito to talklater about liver transplantation. But before that, let me
ask Dr. Okamoto about a matter related to his ﬁeld; thevarious data of cytokines in this patient were collected
at the start of pulse therapy. Dr. Okamoto, in relation
to your previous interpretation, will you give somecomment about this?
Dr. Okamoto: When the sIL-2R level was high,hepatitis seemed clinically controlled. Therefore, the‘‘cytokine storm’’ may have been caused by other factors such as activation of the immune system. The highIL-6 level also suggests that T cells were activated. The
TNF-g level should also have been elevated, however, TNF-a and interferon are easily inactivated unlessthe levels are measured immediately after sampling.
Therefore, the fact that these levels were not elevateddoes not necessarily indicate the absence of the ‘‘cytokine storm’’. The IL-6 and IL-2R levels were high.
These ﬁndings would be adequate to assume an excessive activation of T cells and NK cells.
Dr. Ishii: We looked at one section of the ‘‘cytokine
storm’’. As for Dr. Okamoto’s comment, do you haveany opinion from the clinical aspect, Dr. Yamagishi?
Dr. Yamagishi: The Hb level of the patient wasdetermined to be about 9.5 g/dl on the day of bonemarrow aspiration, and 13.1 g/dl at admission. Thus, theHb level also decreased along with the platelet count.
TNF-a was determined slightly later in samples of serum
stored frozen. The TNF-a level was determined again
on hospital day 40. On this occasion, it was determined
immediately after the blood sample was obtained, andwas found to have elevated to over 20 pg/ml.
Dr. Ishii: Living related liver transplantation has
been performed at our Keio University Hospital for
4–5 years, at least in 55 cases so far. Living related livertransplantation has recently also been actively performed for cases of fulminant hepatic failure. Dr. Saito,
could you please let us know more on this subject,including its current status and its future application.
Dr. Saito: Let me tell you about hepatic transplantation for fulminant hepatitis in Japan. The criteria for hepatic transplantation in acute hepatic failure
have been determined for subjects of cadaver livertransplantation. The ﬁrst process of assessment fortransplantation in such cases considers the following 5
items: (1) The age at the time of occurrence of encephalopathy, 45 years or over; (2) the number of thedays before the occurrence of encephalopathy, 11 daysor more, i.e., whether or not the hepatitis is subacute;(3) prothrombin time (PT), 10% or less; (4) total bilirubin, 18 mg/dl or more; and (5) the ratio of DB to total
bilirubin, 0.67 or less. When 2 of the 5 items are satisﬁed, death is predicted and liver hepatic transplantation is considered.

48

Ishii H, et al: Acute viral hepatitis A and hemophagocytic syndrome

For 5 days, intensive medical treatment is carriedout. When the following 2 items are met at this time
point, the patient is excluded from consideration fortransplantation: (1) Prothrombin time (PT) improved to
50% or more, and (2) encephalopathy improved to
Grade I or milder. When either of the items is not satisﬁed, the patient may still be considered for transplantation.
Cadaver liver transplantation has very rarely been
performed in Japan. Living-related transplantation alsoadheres to a set of criteria. In our Keio University
Hospital, liver transplantation has been performed on
11 patients with acute hepatic failure so far. Unfortunately, 2 of them died thereafter, but 9 patients survived. All of these 9 patients were judged to be deadboth on day one and ﬁve, but their lives were savedby the transplantation. Thus, since transplantation has
become possible and also our medical treatment has
been much improved, the survival rate in cases of acutehepatic failure has rapidly risen with or without livertransplantation. This is the present situation.
Dr. Yamagishi: EB virus marker was examined foragain after the diagnosis of HPS, but similar negative
data were obtained. However, EBV-DNA was not
examined.
There was no evidence of active cytomegalovirus infection, either. Parvovirus B19 was also examined, but
the test was negative.
The acute hepatitis A was considered to be resolving, but HPS occurred as the dose of steroid was being
tapered, suggesting the possibility of the HPS having
been masked by the steroid administration.
Dr. Ishii: We were told that HPS appeared in thesetting of acute fulminant hepatitis. If there are any
questions or comments about the causal relationships
up to this point, we would like to discuss that.
Mr. Izumi: As previously explained by Dr. Okamoto,was this patient considered for peripheral blood stem
cell transplantation (PBSCT) and bone marrow transplantation?
Dr. Yamagishi: After the start of chemotherapy, side
effects including leukocytopenia were observed. However, this resolved to some extent with treatment, and
the PLT and coagulation proﬁle also improved, but thepatient developed cerebral hemorrhage before transplantation could be considered.
Mr. Ikegami: After HPS occurred in this patient,
COP therapy was selected. The treatment could haveincluded other drugs, for example, cyclosporin A, etc.
This patient had fulminant hepatitis A as an underlying
disease, the severity of which was inﬂuenced by the
habitual alcohol drinking. Other body functions may
also have been impaired by the alcohol drinking. I
would like to know whether there were some alternative choices to COP therapy.

Table 3

Summary of Anatomical and Histopathological Findings

1. Hemophagocytic syndrome after chemotherapy
Proliferation of macrophages and hemophagocytosis, severea) Liver (2400 g) with severe bile stasisb) Spleen (1070 g)c) Bone marrow
Related lesions:
Pancytopenia
Hyperplastic bone marrow, mild
Therapies:
Steroid pulse (mPSL)
Chemotherapy (COP therapy: Endoxan 900 mg
þ Oncovin 0.75 mg þ Predonine 60 mg, 1 cool)
2. [Fulminant hepatitis] (2400 g)
Anti-human hepatitis virus type A antibody: (þ)
3. Systemic aspergillosisa) Bilateral severe pneumonia with abscess formation (450,580 g)b) Bilateral renal abscesses (250, 250 g)c) Endocarditis with vegetation (380 g)d) Thyroidal abscesses, right lobe (18.8 g)e) Spleenic abscesses (1070 g)
4. Icteric kidney (250, 250 g)
5. [Brain hemorrhage]

Dr. Ishii: Dr. Okamoto, could you please explain the
choice of the therapeutic strategy, including the reason
for choosing COP therapy.
Dr. Okamoto: As described previously, early judgment of the possibility of self-limiting healing is themost important before you start treatment. If you
think that the self-limiting healing is unlikely, hemopoietic stem cell transplantation with any kind of graft
should be positively considered. While preparing fortransplantation, treatments to suppress hemophagocytic
activity and the release of cytokines from activatedT cells should be provided. The treatment of choiceincludes the administration of steroids with or without
chemotherapeutic agents such as VP-16, cyclophosphamide and vincristine. Cyclosporine should also begiven to suppress the activity of T cells.
Dr. Ishii: Now let us discuss the autopsy ﬁndings.
Dr. Kodama (Pathology): I would like to present thepathological ﬁndings. The autopsy ﬁndings are summarized in Table 1. Bone marrow showed mild hypercellularity and prominent proliferation of macrophages,
which were identiﬁed by immunostaining with antiCD68 antibody (Fig. 5A). Many of the macrophages
had a large volume of cytoplasm which contained
erythrocytes, partially-digested myelocytes and thrombocytes (Fig. 5B and 5C), indicating that these macrophages were hemophagocytic. Macroscopically, the liver appeared swollen, but there was no massive hepatic
necrosis or ﬁbrosis (Fig. 6A). The weight was 2,400 g
and the color indicated intrahepatic bile stasis. Microscopically, numerous macrophages, most of which wereKeio J Med 2003; 52 (1): 38–51

49

Fig. 6 A, Macroscopic appearance of the liver. Liver shows swelling,
but no necrosis or ﬁbrosis. B and C, Microscopic ﬁndings. Enlarged
sinusoids are full of macrophages, which englobed blood cells (B). At
the portal areas, bile stasis is seen (allows). (400)

Fig. 5 Microscopic ﬁndings of the vertebral bone marrow. A,
Immunostaining with anti-CD68 antibody. Note numerous macrophages positively immunostained (allows) in the hypercellular bonemarrow. B and C, Macrophages (allows) containing erythrocytes,
blood cells and vacuoles. (400)

hemophagocytic, were present in the enlarged sinusoids(Fig. 6B). At the portal areas, there was severe bile
stasis (Fig. 6C). Necrotic changes and inﬂammatory

cell inﬁltration were seldom seen in the liver and ﬁbrosis was not observed by Elastica van Gieson staining.
Based on the pathological ﬁndings at autopsy, the fulminant hepatitis diagnosed during the patient’s clinicalcourse was believed to have been cured. Thus, thepathological diagnosis of the liver was hemophagocytic
syndrome. The spleen was huge, weighing 1,020 g,
about 10-fold larger than a normal spleen. There weremany macrophages which had englobed blood cells.
The bilateral lungs showed severe pneumonia with

50

Fig. 7 A, Macroscopic appearance of the lung. The lungs show severe pneumonia with various-sized abscesses (allows). B, Grocott’s
staining of the lung. Note that there are a lot of mycelia of Aspergillus,
which branch at acute angles (40 degree). (400)

various-sized abscesses (Fig. 7A). Multiple abscesses
were also found in the kidneys, thyroid and spleen. Microscopically, all of the abscesses had necrosis, prominent neutrophil inﬁltrations and mycelia of fungus,
which were stained by Grocott’s staining (Fig. 7B). The
mycelia branched at acute angles (@40 ), which is speciﬁc for Aspergillus. The heart showed endocarditis
with small mural vegetation in the left ventricle, and thebase of the vegetation had abscesses with mycelia ofAspergillus. Thus, the patient was considered to havesuffered from sepsis.
Hemophagocytic syndrome is commonly associatedwith viral infections including Epstein-Barr virus, human hepatitis virus types B and C, and also with carcinomas and malignant lymphomas. However, hemophagocytic syndrome associated with hepatitis virus type A
infection is rather rare, and only a few cases have been
so far reported. In the present case, we could exclude
the possible association of Epstein-Barr virus infection,
malignant tumors and malignant lymphoma.
In summary, we have presented a case of hemophagocytic syndrome, which emerged during the treatment
for fulminant hepatitis caused by hepatitis virus type A

Ishii H, et al: Acute viral hepatitis A and hemophagocytic syndrome

infection. Although the fulminant hepatitis was almost
cured, immunosuppressive therapy for hemophagocytic
syndrome induced Aspergillus infection and ﬁnally thepatient died of multiple organ failure due to sepsis.
Dr. Ishii: Thank you for your comments, Dr.
Kodama.
The patient had acute hepatitis A, which became
fulminant. However, fulminant hepatitis itself could becontrolled for the time being. However, HPS appeared,
didn’t it?
Dr. Yamagishi: Yes, it did.
Dr. Ishii: Usually, it is impossible for autopsied liverof fulminant hepatitis to weigh as much as 2,400 g. Fulminant hepatitis usually shows acute liver atrophy. So
in fulminant hepatitis patients we have experienced,
who were subjected to autopsy, the liver weighed 500 g
or 700 g. This fact indicates massive hepatic necrosis.
When observing the pathological ﬁndings, various
changes replacing the ﬁndings can be observed with attention. Dr. Saito and Dr. Okamoto, please give somecomments from your respective standpoints about the
aforementioned pathological ﬁndings.
Dr. Okamoto: We have treated 6 patients with HPS,
but only one patient survived after the treatment. What
we have learned during the treatment is that controllingof infection is important. In patients with HPS it is difﬁcult to conﬁrm the presence of infection, because oneof the symptoms of HPS is high fever, furthermore, thepatients are usually pancytopenic, and receive highdose steroids as a part of treatment. Those makethe patients more susceptible to infections. Therefore,much attention must be constantly paid to infection.
This patient had Aspergillus pneumonia. In the patients
whom we treated before, immunosuppressants at a highdose have been used, and eventually about half of themdied with fungal or Pneumocystis infections.
Since this patient had pneumonia in the lower lobe,
early detection may have been difﬁcult by chest X-ray.
However, it has become possible to detect fungal
infection earlier by monitoring b-glucan, Aspergillus
antigen, or PCR. Recently, newer antifungal agents
such as voriconazole and liposomal amphotericin B havebecome commercially available, and the results of thetreatment of Aspergillus infection have been markedly
improved. If this patient had overcome the infection, hemight have recovered.
Dr. Saito: After having this patient, the treatment
environment for patients with fulminant hepatitis has
been changed to an aseptic room. When listening to thepathological ﬁndings today, I am really impressed thatthe liver is an organ with the very high ability to regenerate. The hepatic encephalopathy was very severe,
the bilirubin level was elevated, and prothrombin time(PT) was decreased. In other words, hepatocytic necrosis, which was so massive that would induce hepaticKeio J Med 2003; 52 (1): 38–51

Table 4
Pt No.

51

HPS Related Hepatitis Virus A
Age

Sex

Fever
C



1
2
3
our case

20
23
40
36

F
M
M
M

Hepatosplenomegary

GOT
IU/l

GPT
IU/l

LDH
IU/l

TB
mg/dl

HAIgM

Ferritinng/ml

Plt/ml

þ
þ
þ
þ

3270
355
2250
4130

1880
367
2000
5780

5480

20.0
31
1.7
43

þ
þ
þ
þ

2287

49000
10000
37000
<10000

39
39.5
þ
40

3482
1640

4652
4080

Pt No.

Therapy

Underlying disease

Outcome1
2
3
our case

Steroid, VP-16
Steroid
None
COP TxStill disease
HCV
None
None

Died (liver failure, DIC)
Died (GI bleeding, DIC)
Survived
Died (Brain hemorrage)

1. Journal of Medical Virology, 1993.
2. The American Journal of Gastroenterology, 1995.
3. The American Journal of Gastroenterology, 1998.

failure, was present, but in spite of this, the liver was
restored to such a level within 2 months. I thought thisdemonstrated that hepatocytes of the necrotic site areregenerated along with absorption of ﬁbrosis.
Dr. Ishii: Thank you for your comments, Dr. Saito.
In addition, the long history of heavy alcohol drinking cannot be ignored in this patient. With continuous
heavy drinking of a large quantity of alcohol for so longthe immunological functions may be impaired, eventhough this patient was still only in his 30’s. Alcohol
also greatly suppresses cellular immunity, in the sensethat the reticuloendothelial function is disturbed. In thisbackground, the patient also had infection with hepatitis A virus.
Cases of HPS associated with hepatitis A collectedby Dr. Yamagishi.
Dr. Yamagishi: As for reported cases related to
HAV, a review of literature revealed 3 patients reported in the world by the year 2000 (Table 4). However, one of them had Still’s disease and the other one
had HCV infection. The remaining one patient had nounderlying disease, and showed favorable prognosis.

The disease in this patient was self-limiting and the patient survived almost without any treatment. Two other
patients received administration of steroids or VP-16,
but nevertheless died. Our present patient also developed cerebral hemorrhage and died.
Dr. Ishii: This patient showed a very uncommon
course in various senses. Professor Okada, will you
please give your ﬁnal comments about the present
patient?
Dr. Okada (Pathology): The pathology of the liver inthe present case is very interesting. We expected acuteliver atrophy showing massive hepatic necrosis, but theliver at autopsy had ﬁndings suggestive of the convalescent stage of acute hepatitis. This was a surprisingﬁnding, but we must keep in mind that almost complete
repair can occur in damaged livers, even in fulminant
hepatitis. In the present case, we have also learned theprecise mechanisms of hemophagocytic syndrome. We
hope that hemophagocytic syndrome may be cured bytarget treatments in the near future.
Dr. Ishii: Thank you. I now conclude today’s CPC.
Thank you very much for your attention.