Liver Volume 60 No.

1 39―45(2019) 39:39

<Report of medical case>

A case of hepatocellular carcinoma diagnosis

using direct oral anticoagulants

Tsukasa Karasuyama *, Yuichi Honma, Kosei Hidaka , Kahori Morino,

Yudai Koya, Masaaki Hiura, Michihiko Shibata, Masaru Harada

Abstract: A 65-year-old male. The patient had received treatments with Transcatheter Arterial
Chemo-Embolization (TACE) and radiofrequency ablation for hepatocellular carcinoma since the
age of 59. At the age of 62, his protein induced by vitamin K absence or antagonist-II (PIVKA-II)
was not measured because of the adoption of warfarin potassium for portal vein thrombosis
treatment. In May at the age of 64, a recurrence of hepatocellular carcinoma measuring 13 mm in
size in liver S7 and 12 mm in liver S8 was found, hence TACE was performed. Afterward, the
patient was free from recurrence. In November of the same year, a contrast-enhanced CT scan of
the abdomen revealed a hypo-absorption area of 30 mm in size with an indistinct boundary without
contrast effect in the right lobe of the liver (S5 -6). When warfarin potassium was changed to
edoxaban and PIVKA-II was measured, its level was as high as 952 mAU/mL. PET-CT showed
increased accumulation at the same site, and the patient was diagnosed with a recurrence of
hepatocellular carcinoma, suggesting that poorly differentiated hepatocellular carcinoma had
progressed relatively rapidly. Since α-fetoprotein and PIVKA-II are indicators of tumor
progression in patients with hepatocellular carcinoma, the adoption of direct oral anticoagulants
was considered advisable.

Key words: hepatocellular carcinoma, PIVKA-II, direct oral anticoagulants, warfarin potassium,
poorly differentiated

Background Description

In addition to abdominal ultrasonography, Patient: 65- year- old, male.

computed tomography (CT), and magnetic Chief complaint: None.
resonance imaging (MRI), the measurement of Past medical situation: Warfarin
tumor markers is also beneficial in the potassium for portal vein thrombosis since the
diagnosis of hepatocellular carcinoma 1). age of 62.
When patients are taking warfarin potassium, Life history: drinking habit: 1 masu
protein induced by vitamin K absence or (approximately 1.8L) of Japanese sake per day
antagonist-II (PIVKA-II) cannot be used as a (in 32 years), smoking habit: 20 cigarettes per
tumor marker, which may cause a delay in the day.
diagnosis of hepatocellular carcinoma, being Family history: None noted.
only positive for PIVKA-II. In this case, we Current medical situation: The patient
experienced a recurrence case of was diagnosed with hepatitis C cirrhosis
hepatocellular carcinoma that progressed around the age of 40 and had a history of
rapidly with multiple extrahepatic metastases interferon treatment at another hospital,
after a switch from warfarin potassium to a
direct oral anticoagulant (DOAC), because of
high PIVKA-II levels. Since diagnosis of
poorly differentiated hepatocellular carcinoma
based on imaging is challenging, measurement
of tumor markers may be beneficiary for early
diagnosis. This time we experience a potential
case of anticoagulation with DOAC, we will
report it as well as review some relevant
literature.
Third Department of Internal Medicine,
University of Occupational and
Environmental Health.
*Corresponding author:
karasuyama@med.uoeh-u.ac.jp <Date of
receipt July 4, 2018><Date of execution
October 25, 2018>
however, the details of the treatment and its
course were unknown and no negative reaction
to hepatitis C virus was observed. He had a
history of heavy drinking for 32 years until the
age of 62. Since the age of 59, he had
repeatedly undergone Transcatheter Arterial
Chemo-Embolization (TACE) and
radiofrequency ablation (RFA) for the
treatment to hepatocellular carcinoma. Since
the age of 62, he had been taking warfarin
potassium for portal vein thrombosis. The
portal vein thrombosis located from the main
trunk to the right branch of the portal vein, and
the PT-INR ranged in the region of 1.6 and 2.0
on 1 mg/day of warfarin potassium. The
thrombus in the main trunk of the portal vein
showed a slight reduction in size, and the
patient recovered without any significant
symptom afterward. In May at the age of 64, a
recurrence of hepatocellular carcinoma was
found in S7 and S8 of the liver, measuring 13
mm and 12 mm, respectively, and the patient
was treated with TACE. A contrast-enhanced
CT in the arterial phase in November showed
the appearance of an irregular pale contrast
mass approximately 30 mm in size in the right
lobe of the liver (S5-6), the increase in ascites,
multiple nodules in
40:40 Liver Volume 60 No. 1 (2019)

Table 1 Laboratory data on admission

Hematology
WBC 6200 /μL BUN 14 mg/dL
Neut 60.3 % Cre 0.8 mg/dL
Eos 6.6 % Na 136 mEq/L
Baso 0.8 % K 3.5 mEq/L
Lympho 18.1 % Cl 105 mEq/L
RBC 365×104 /μL Serology
Hb 12.5 g/dL CRP 1.1 mg/dL
Ht 36.8 % Coagulation
PLT 14.8×104 /μL PT 54.2 %
PT-INR 1.34
Biochemistry D-dimer 26.9 μg/mL
TP 7.1 g/dL Tumor markers
Alb 2.1 g/dL AFP 11.1 ng/mL
T-Bil 1.1 mg/dL PIVKA-II 22469 mAU/mL
D-Bil 0.5 mg/dL Virus markers
AST 102 U/L HBs Ag (-)
ALT 45 U/L HBc Ab (+)
LDH 259 U/L HCV Ab (+)
ALP 280 U/L HCV RNA 6.5 LogU/mL
γ-GTP 46 U/L

both lung fields, right pleural effusion,
swelling in the right hilar lymph node, and
mediastinal lymph node. On the grounds of a
claim of fatigue from the patient after taking
warfarin potassium, it was replaced with
edoxaban. The result of the PIVKA-II
measurement showed a high value of 952
mAU/mL. The α-fetoprotein (AFP) was in the
normal range. PET-CT showed
hyperaccumulation in the same area, and a
diagnosis of recurrence and progression of
hepatocellular carcinoma was made.
Nevertheless, at the time of diagnosis, the liver
functional reserve was reduced to Child-Pugh
grade C, which caused other therapies, such as
Transhepatic Arterial Infusion (TAI) and
molecularly targeted agents, deemed difficult
to adapt to, we started treatment with
tegafur/uracil (UFT ○ R ) 200 mg /day. In
January at the age of 65, given the PIVKA-II
breathing sounds were weak. The abdomen
was slightly distended, soft, and no pain. The
liver and spleen were impalpable. No edema in
the lower legs was observed.
Laboratory data on admission (Table 1):
Elevation of liver enzymes and a decrease in
PT were observed, and the tumor markers were
AFP 11.1 ng/mL and PIVKA-II 22,469
mAU/mL, which were markedly elevated.
Abdomen contrast-enhanced
ultrasonography test (Fig. 1): A 30 mm
hypoechoic area with an indistinct boundary
was found in the right liver lobe. Sonazoid
imaging showed irregular, faint, intense
staining in the arterial phase and a defect in the
Kupffer phase (arrow head).
Abdomen contrast-enhanced CT scan
(Fig. 2): Multiple masses (arrow head) in both
lobes of the liver with irregular faint contrast
in the arterial phase and a washout detected in
 climbed to 6795 mAU/mL, the dose of UFT○ R the venous and equilibrium phases were found.
was increased to 300 mg. In February, PIVKA-
II was further elevated at 22469 mAU/mL, and
CT showed hypo-absorption areas in the right
liver lobe, multiple nodular shadows in both
lung fields, and an increase in lymph node
metastasis in the hilar and mediastinal areas.
The patient was hospitalized in March of the
same year with a plan to receive TAI using
R ) treatment. There was no
cisplatin (Iacol ○
significant change or deterioration in portal
vein thrombosis after switching to edoxaban.
Conditions on admission: Height 168 cm,
weight 76.6 kg, BMI 27.2 kg/m2, body
temperature 36.6 C, pulse rate 68/min, blood
pressure 115/74 mmHg, respiratory rate
18/min, clear consciousness, no anemia in
palpebral conjunctiva, no jaundice in bulbar
conjunctiva. Superficial cervical lymph nodes
were impalpable. In the right lung field,
A case of hepatocellular carcinoma diagnosis using direct oral anticoagulants
PET- CT scan (Fig. 3): A progressing
accumulation (standardized uptake value =
6.8) was found around the site of lipiodol
deposition in the right lobe of the liver. An
accumulation in the mediastinum was also
found and was considered a lymph node.
Hepatic angiography test (Fig. 4): Right
hepatic arteriography showed multiple tumor
staining images in the main right lobe.
Clinical course: The patient underwent
TAI on the second hospital day. His overall
condition was good, with no evidence of
decreased hepatic reserve or renal dysfunction,
and he was discharged on the 13th day. After
about 3 weeks, PIVKA-II decreased to 3552
mAU/mL (Fig. 5),
41:41
 Fig. 1 Contrast-enhanced ultrasonography findings. The mass lesion of
the liver was slightly hypoechoic in B-mode (a, c), irregularly enhanced
in the arterial phase (b), and showed a defect in the Kupffer phase (d).
possibly due to the therapeutic effect of TAI.
The Study
It is known that frequent TACE and RFA
for hepatocellular carcinoma can cause poorly
differentiated hepatocellular carcinoma such
as sarcomatoid hepatocarcinoma. It is highly
malignant, with rapid growth. Therefore, it is
aggressively progressing, resulting in highly
likely local recurrence and distant metastasis,
with an unpleasant prognosis2). A pathological
diagnosis could not be made in this case
because of ascites and anticoagulation therapy.
Moreover, the images revealing a mass in the
right lobe of the liver with poor contrast in the
arterial phase of a contrast-enhanced CT scan
was not only an atypical image of classic
hepatocellular carcinoma, but it was also
difficult to be distinguished from the progress
of previous treatments and a recurrence of
hepatocellular carcinoma. However, thanks to
the measurement of PIVKA-II due to the
change of anticoagulation therapy to DOAC,
the diagnosis of hepatocellular carcinoma was
concluded. Subsequently, the rapid growth of
the mass and extrahepatic metastasis were
observed, suggesting a rapid progression of
poorly differentiated hepatocellular
carcinoma. In general, AFP and PIVKA-II are
helpful tumor markers in hepatocellular
carcinoma, and since PIVKA-II was reported
to be a frequent symptom of hepatocellular
carcinoma in 1984, it has been used as useful
tumor markers in clinical practice 3). The
sensitivity and specificity in early-stage
hepatocellular carcinoma were reported to be
77%，
and 82%, respectively, both higher than those
of AFP 4). In addition, elevated PIVKA-II
strongly correlates with tumor progression and
has been reported to be an independent
prognostic factor 5). Hepatocellular carcinoma
progression and metastasis have been shown to
be associated with epithelial-mesenchymal
transition (EMT) 6), it has been demonstrated
that vitamin K uptake is impaired and PIVKA-
II is produced in this process 7). Therefore, the
measurement of PIVKA-II is believed to be
useful for predicting the progression and
metastasis of hepatocellular carcinoma as well
as the phenotypic change to poorly
differentiated hepatocellular carcinoma
including sarcomatoid changes. However, the
level of PIVKA-II is also known to be elevated
in patients with impaired vitamin K
absorption, such as obstructive jaundice and
intrahepatic cholestasis, as well as those taking
warfarin potassium and receiving antibacterial
agents. The level is reported to be elevated in
alcohol-induced liver injury as well 8). In this
case, the abstinence from alcohol had been
maintained by the patient for about 3 years, the
effect of alcohol-inducing factor was not
considered but the illness status of
hepatocellular carcinoma.
In fact, even in this case, the fluctuation of
PIVKA-II level during the course, and a
marked increase before treatment was
observed, the drop in level after the treatment,
hence, was considered as a reflection of the
effect of TAI treatment. On the other hand,
AFP levels were slightly elevated after
treatment, but this was considered to reflect the
effects of lymph nodes and lung metastases.
42:42 Liver Volume 60 No. 1 (2019)

42:42 Liver 60 Volume No. 1 (2019)

Fig. 2 Contrast-enhanced computed tomography of the liver. The liver mass was slightly and irregularly en-
hanced in the arterial phase (a, d, g) but not enhanced in the portal phase (b, e, h) or equilibrium phase (c, f, i).

Fig. 3 PET-CT demonstrating accumulation (standardized uptake max value,

6.8) of 18F-FDG in the liver mass of right hepatic lobe (a) and in the
mediastinal lymph node (b).
 A case of hepatocellular carcinoma diagnosis using direct oral anticoagulants 43:43

Fig. 4 Hepatic angiography showing tumor stains in the liver.

UFT 300 mg/ Admission

PIVKA- II UFT 200 mg/ day TAI AFP
(mAU/mL) day (ng/mL
)

64-year- 64-year 64-year- 64-year- 65-year 65-year- 65-year-

old -old old old -old old old
Sep Oct Nov Dec Jan Pre-TAI Post-TAI

Fig. 5 Clinical course of tumor markers.

 Warfarin potassium is often dosed for
anticoagulation in patients with hepatocellular
carcinoma who also have atrial fibrillation. In
those cases, PIVKA-II will not be an indicator
for observing the progress. Warfarin potassium
is also used as anticoagulant therapy for portal
vein thrombosis, nevertheless about 3/4 of
patients have cirrhosis as the underlying illness
9). It is also understood that the PIVKA-II
measurement for many patients with
hepatocellular carcinoma or those at its high
risk may be impossible to be conducted. There
have been a number of reports of DOAC
treatment for portal vein thrombosis, with the
disappearance of blood clots after 6 months of
treatment 10). In addition, DOAC has already
been used for the treatment of non-valvular
atrial fibrillation. The switch from warfarin
potassium
to DOAC has many advantages, such as
unnecessary dose adjustment, reduced dietary
restrictions, and unnecessary periodic blood
tests to confirm therapeutic efficacy. The
efficacy of drug therapy for portal vein
thrombosis varies greatly depending on the
timing of treatment, the amount and nature of
blood clots 9). The current situation is that no
effective treatment has been established for the
blood clots, which are considered to have
existed persistently and become systematized
as in this case. The use of DOACs for portal
vein thrombosis treatment is novel, and there
are also no randomized controlled trials
comparing their therapeutic efficacy to that of
potassium warfarin. However, recent reports
showed that DOACs, including the edoxaban
used in this study, had similar efficacy as

44:44 Liver 60 Volume No. 1 (2019)

conventional treatments such as low molecular vasion. J Hepatol 2015; 62: 848―854
weight heparin and vitamin K inhibitors in
moderating the uptrend, and reoccurrence, and
preventing bleeding risk of portal vein 5) Xu JF, Liu XY. PIVKA-II is an independent
thrombosis during treatment 11). The prog-
therapeutic effect of DOAC on portal vein
thrombosis treatment is promising in the nostic factor for overall survival of HCC
future. Considering the benefit of PIVKA-II patients and maybe associated with epithelial-
measurement in the periodic follow-up after mesenchymal transition. J Hepatol 2015; 63:
treatment of hepatocellular carcinoma, as the 1040― 1053
case in this paper, proactively switching from
warfarin potassium to DOAC and measuring 6) Giannelli G, Koudelkova P, Dituri F, et al.
PIVKA-II would be considered to contribute to Role of epithelial to mesenchymal transition in
the early detection of tumor recurrence and hepatocel- lular carcinoma. J Hepatol 2016;
progression. 65: 798―808

Conclusion 7) Murata K, Suzuki H, Okano H, et al.

Hypoxia- induced des-gamma-carboxy
We experienced a case of rapidly prothrombin produc- tion in hepatocellular
progressing hepatocellular carcinoma in which carcinoma. Int J Oncol 2010; 36: 161―170
the change from warfarin potassium to DOAC
was thought to be diagnostically beneficial. 8) 藤木真人，高田泰次，伊藤孝司，他.肝
Given that poorly differentiated hepatocellular 移植レシピ エントにおける肝細胞癌再発
carcinoma may be difficult to detect by relying 予測因子としての PIVKA-II 測定の臨床的
independently on imaging data, the adoption of
DOAC and measurement of AFP along with 意義.日本消化器外科学会 雑誌
PIVKA-II in patients who require oral 2007;40:1549―1556
anticoagulant medication may contribute to the
detection of recurrence or progression of 9) 小嶋聖一郎，高清水眞二，渡辺勲史，
hepatocellular carcinoma at an early stage. 他.本邦にお ける門脈血栓の診療動向.肝
胆膵 2016;72:313― 318
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 A case of hepatocellular carcinoma diagnosis using direct oral anticoagulants 45:45

A case of hepatocellular carcinoma diagnosis

using direct oral anticoagulants
Tsukasa Karasuyama* , Yuichi Honma, , Kosei Hidaka , Kahori Morino,
Yudai Koya, Masaaki Hiura, Michihiko Shibata, Masaru Harada

We examined a 65 year-old-man diagnosed with hepatocellular carcinoma (HCC) 6 years ago,

who had undergone repeated transcatheter arterial chemoembolization and radiofrequency
ablation procedures. The patient was taking warfarin for the portal vein thrombosis, and thus
lacked PIVKA-II measurements. Contrast-enhanced ultrasonography and computed tomography
showed a 30-mm unenhanced liver tumor in the right hepatic lobe. We prescribed edoxaban instead
of warfarin and measured his PIVKA-II values. The serum PIVKA-II level was high (952
mAU/mL). PET-CT revealed a high level of 18F-FDG accumulated in the tumor. Therefore, we
diagnosed the patient to have HCC recurrence and assumed that the poorly differentiated hepa-
tocellular carcinoma had rapidly progressed. In HCC patients, PIVKA-II has been useful as an
index maker of the progression and of the malignant potential of tumors. We recommend the use
of direct oral anticoagulants for patients with HCC.

Key words: hepatocellular carcinoma PIVKA-II direct oral anticoagulants

warfarin potassium poorly differentiated

Kanzo 2019; 60: 39―45

_________________________________________
Third Department of Internal Medicine, School of Medicine, University of Occupational and
Environmental Health, Kitakyushu, Japan
*Corresponding author: karasuyama@med.uoeh-u.ac.jp

___________________________

C 2019 The Japan Society of Hepatology

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