Journal of
Gastroenterology and Hepatology Research
Journal of GHR 2020 June 21; 9(3): 3234-3237
ISSN 2224-3992 (print) ISSN 2224-6509 (online)
Online Submissions: http: //www.ghrnet.org/index./joghr/
doi: 10.17554/j.issn.2224-3992.2020.09.933
CASE REPORT
Hepatocellular Carcinoma Arising After Hepatitis B
Seroconversion without Cirrhosis, When and How Surveillance
is done?
Muhammad Begawan Bestari , Ignatius Ronaldi Joewono , Ivonne Golda Palungkun , Siti Aminah Abdurachman
1
1
1 Division of Gastroenterohepatology, Department of Internal
Medicine, Hasan Sadikin General Hospital, Faculty of Medicine,
Universitas Padjadjaran, Bandung, Indonesia;
2 Santo Boromeus Hospital Bandung, Bandung, Indonesia.
2
1
seroconversion, however HBsAg persisted at lower levels. The
treatment then switched to PegIFN α-2a 180 mg for 1 year, in which
resulted in HBsAg seroclearance with normal abdominal ultrasound
and hepatic elastography showed no sign of cirrhosis. Three months
later, he developed anti-HBsAg and subsequently the patient was
loss to follow up. After 2 years the patient showed up with right
upper quadrant pain. Abdominal ultrasound and CT scan were
performed in which suggestive of HCC confirmed by liver biopsy.
Two months after admission the patient experienced esophageal
varices ruptured and treated with ligation. With this development of
HCC after seroconversion, it is crucial for physicians to establish the
surveillance criteria for resolved Hepatitis B patients.
Conflict-of-interest statement: The authors declare that there is no
conflict of interest regarding the publication of this paper.
Open-Access: This article is an open-access article which was
selected by an in-house editor and fully peer-reviewed by external
reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work noncommercially, and license their derivative works on different terms,
provided the original work is properly cited and the use is noncommercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Key words: Hepatocellular Carcinoma; Hepatitis B; Seroconversion;
Surveillance
© 2020 The Authors. Published by ACT Publishing Group Ltd. All
rights reserved.
Correspondence to: Muhammad Begawan Bestari, Division of
Gastroenterohepatology, Department of Internal Medicine, Hasan
Sadikin General Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia.
Email: begawanb@yahoo.com
Telephone: +62816629795
Bestari MB, Joewono IR, Palungkun IG, Abdurachman SA. Hepatocellular Carcinoma Arising After Hepatitis B Seroconversion without
Cirrhosis, When and How Surveillance is done? Journal of Gastroenterology and Hepatology Research 2020; 9(3): 3234-3237 Available
from: URL: http://www.ghrnet.org/index.php/joghr/article/view/2873
Received: April 18, 2020
Revised: May 3, 2020
Accepted: May 8, 2020
Published online: June 21, 2020
INTRODUCTION
Hepatitis infection contributed to 1.34 million deaths in 2015, even
higher than HIV based on WHO Global Hepatitis Report 2017[1]. In
Indonesia, approximately 18 million people chronically infected with
Hepatitis B Virus (HBV)[2]. The risk for developing Chronic Hepatitis B (CHB) infection is age dependent, approximately 90% infants
become chronically infected and only <5% adults developed chronic
HBV infection, with the long-term consequence such as cirrhosis and
hepatocellular carcinoma (HCC)[3,4]. Hepatitis B is a major contributor for the development of hepatocellular carcinoma, approximately
60% of all cases in Asia and Africa[5].
In patients with Chronic Hepatitis B infection, seroconversion
of HBeAg to the development Anti-HBeAg is associated with low
HBV-DNA levels and remission of the disease in the majority of the
patients. In some uncommon cases the patients also undergo HBsAg
ABSTRACT
Approximately 18 million people chronically infected with
Hepatitis B Virus (HBV) in Indonesia. HBV is a major contributor
for the development of hepatocellular carcinoma (HCC). The
therapy endpoint for chronic HBV is HBsAg seroclearance or
seroconversion. However, in small percentage, HCC can still
develop even after seroconversion. This is the first case of such
occurrence reported in Indonesia. We report a case of 57-years old
male diagnosed with chronic HBV infection 9 years ago by serologic
marker and quantitative HBV DNA. The patient was given Entecavir
therapy for 6 years and resulted in HBV DNA clearance and HBeAg
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Bestari MB et al . A Case Report after Hepatitis B Seroconversion
seroclearance or even seroconversion to Anti-HBsAg that can occur in 6.77% after antiviral therapy and even lower spontaneously.
However, since HBV can still present at low replicative and transcriptional levels, therefore causing HCC which is the most frequent
liver-related complication after HBsAg seroclearance with the rate of
1.86%[6]. This is the first case of such occurrence reported in Indonesia.
CASE DESCRIPTION
A 57-year old male with abdominal pain on right upper quadrant
was diagnosed with HBV 9 years ago by serologic marker HBsAg
3688 IU/mL, HBeAg (+), anti HBeAg (-), HBV DNA 2.57 × 107
IU/mL, AST 560 IU/L, and ALT 440 IU/L. After entecavir therapy
for 6 years HBV DNA clearance and HBeAg seroconversion were
achieved, however HBsAg persisted at 19.66 IU/mL. The treatment
then switched to PegIFN α-2a 180mg for 1 year. The patient reached
HBsAg seroclearance at the end of treatment with normal abdominal
ultrasound (US) and hepatic elastography of 5.6 kPa. Three months
later he developed anti HBsAg 14 mIU/mL. The patient was loss to
follow up for 2 years, until current symptoms appeared with serologic markers HBsAg (-), anti HBsAg 121.5 mIU/mL, HBeAg (-),
anti HBeAg (+), anti HBcAg (+), HBV DNA (-), anti HCV (-) and
AFP 1.93 IU/mL. US suggestive HCC in right lobe and CT scan
suggestive of HCC with multiple nodules on both lobes, minimal
ascites and portal vein thrombus. Liver biopsy revealed columnar
cells arranged in irregular tubular pattern, with nuclear polymorphism, coarse chromatin and presence of mitotic activity (Figures
1-3). Stroma consisted of fibrous collagen bands, with lymphocytes
and polymorphonuclear neutrophils. No family history of HCC nor
habitual alcohol intake identified. Two months after current admission, the patient experienced hematemesis from ruptured esophageal
varices which successfully treated with endoscopic ligation.
DISCUSSION
This is the first case of hepatocellular carcinoma arising from resolved hepatitis B after HBsAg seroconversion and seroclearance reported in Indonesia. This patient has been successfully reached ideal
endpoint of therapy using switch strategy of entecavir and Peg-IFN
α-2a. HBsAg seroclearance is achieved by the end of therapy with
no cirrhosis, and HBsAg seroconversion developed three months
afterward. Nevertheless, HCC still developed in this patient in period
of two years after HBsAg seroconversion and seroclearance. The risk
of Hepatocellular carcinoma (HCC) is 15-20 times greater among
HBV-infected individuals compared with the uninfected population.
[7]
The chance of developing HCC is significantly lower with patients
that has undetectable HBV DNA, HBsAg seroclearance, and HBeAg
seroconversion.
However, 1.86% of patients with seroclearance still developed
HCC[8,9]. Covalently closes circular DNA (cccDNA) may still persist
intrahepatically, also known as occult hepatitis B infection (OBI).
Unfortunately, cccDNA examination was not commercially available
and did not performed in this patient. Study of OBI in Indonesia is
still limited, because it is not commonly practiced. Most of the study
are using only serum HBV DNA, while HBV DNA in the hepatocyte
were not measured. Despite the limitations, a study by Thedja, et al.
found 8.1% prevalence of OBI in regular blood donors.[10] The presence of HBV DNA at low replicative and transcriptional level is a
risk factor for HCC development, and studies show that HCC is the
most frequent complication related to liver after HBsAg seroclearance[11,12].
Figure 1-3 Histopathologic examination of the tissue sample. (1) Liver
biopsy (low power field/100x) revealed presence of tumor cells and
cirrhosis. (2) Tumor cells (High Power Field/ 400x) columnar cells arranged
in irregular tubular pattern, with nuclear polymorphism, coarse chromatin,
and presence of mitotic activity. (3) Infiltration of inflammatory cells
(mononuclear and polymorphonuclear) on fibro collagen septa.
Similar reported cases by Wong et al[13] with same gender and age
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Bestari MB et al . A Case Report after Hepatitis B Seroconversion
group which is ≥ 50 years old, in their case the patient was treated
with lamivudine for 3 years which resulted in HBsAg seroconversion
and undetectable HBV DNA. However, after 7 years of seroconversion the patient presented with HCC with detectable HBV DNA,
which remained undetected in our case. Another case by Shigematsu,
et al[14]. mentioned the development of HCC after 17 years of seroconversion using steroid therapy, but the patient had liver fibrosis by
the time seroconversion occurs. The last similar case that we found
was spontaneous seroconversion from HBV and HDV superinfection,
yet after 5 years developed HCC with HBsAg remained negative[15].
This highlights the urgency of surveillance for HCC, even in
patient with HBsAg seroclearance. This patient was loss to follow
up for two years before diagnosed with HCC. APASL, AASLD and
EASL suggesting US examinations with or without AFP for surveillance of HCC every 6 months for high risk group. US result in this
patient is suggestive of HCC in the right lobe, but AFP result was 1.93
IU/mL, which is below expected value for suggestive of HCC. AFP
sensitivity and specificity are 22.4% and 99.4% at 200 ng/mL (165.28
IU/mL) respectively, while US are 58-89% and > 90% respectively[5,16]. Combined examination resulting in higher sensitivity of 63%
but lower specificity of 84%[17]. Despite the high specificity, study by
Chan, et al[18] showed AFP has low negative predictive value (NPV)
of 27.3% in ruling out HCC in HBV infected patient, which give rise
to false negative result that happened in this patient[16,18]. There are
other serologic markers such as Des-gamma-carboxyprothrombin
(DCP), also known as prothrombin induced by vitamin K absenceII (PIVKA-II); Lens culinaris agglutinin-reactive fraction of AFP
(AFP-L3); Glypican-3 (GPC3) and other proposed tumor markers.
Nevertheless, none of these are recommended by EASL, APASL, or
AASLD for surveillance of HCC development at the moment.
Justifications regarding follow up are whether risk of HCC sufficient to overcome the cost. In AASLD and APASL guideline, HCC
surveillance considered to be cost-effective when annual risk of HCC
exceeds 0.2% per year or all patients in cirrhosis condition, yet it
remains inconclusive for patients with HBsAg seroclearance like this
patient[7,19]. Meta-analysis study by Kuang et al[6] identified cirrhosis,
male gender, and age ≥50 years at HBsAg seroclearance are the risk
factors, while family history of HCC may also be a risk factor in developing HCC after seroclearance. Therefore, surveillance is deemed
necessary for patients with any of these risk factor. We suggest Asian
descent to be more susceptible to develop HCC even after seroconversion and seroclearance, since the incidence is higher in Asian
race[6,9]. Further demographic study is required to confirm this statement to narrow down the surveillance criteria.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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CONCLUSIONS
This case demonstrated the development of HCC from resolved
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ACKNOWLEDGMENT
We would like to thank the patient for allowing us to share the
clinical history.
Statements
This case has been published as abstract on American Journal of
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manuscript has not been submitted/published elsewhere.
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Bestari MB et al . A Case Report after Hepatitis B Seroconversion
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