Journal Reading Homework Journal of Hepatocellular Carcinoma

2021:8

Name : Shofia Widya Murti

Moderator : Fajar Wasilah
Day/Date : Wednesday/April 14th, 2021
Department of Clinical Pathology, Faculty of Medicine, Padjajaran University, Dr. Hasan
Sadikin Hospital Bandung

Association of Postoperative Biomarker Response with Recurrence and

Survival in Patients with Hepatocellular Carcinoma and
High Alpha-Fetoprotein Expressions (>400 ng/ml)
Liang L, Wang M, Zhang Y, Lau W, Shen F, et al.

1. How is the mechanism Hepatitis B and Hepatitis C become Hepatocellular

Carcinoma? (dr. Christian)

Answer :

Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infection can cause chronic

injury to the liver, with subsequent progression to severe fibrosis and cirrhosis. The

presence of cirrhosis is a major risk factor for the development of Hepatocellular

Carcinoma (HCC). However, HCC can occur in the absence of cirrhosis, suggesting that

both HBV and HCV may be directly involved in hepatocarcinogenesis. HBV is a DNA

virus and HCV is an RNA virus, these two viruses are sufficiently cause cancer via

different mechanisms at the molecular level. The mechanisms by which these viruses

cause cancer are likely to involve complex interactions between the virus and the human

host.
Figure 1. Proposed mechanisms of hepatocarcinogenesis related to hepatitis B virus (HBV)
and hepatitis C virus (HCV). HCC, hepatocellular carcinoma.

a. Role of HBV

HBV likely causes HCC via both indirect and direct pathways. In the former, HBV

incites chronic injury to the hepatocytes, with continuous necro-inflammation and

regeneration activity and a resultant increase in hepatocyte turnover. The net effect of

this, is the accumulation of potential critical mutations in the hepatocyte genome, with

subsequent malignant transformation and clonal expansion, leading to HCC. Because

HBV contains partially double stranded-DNA, it can directly cause HCC by

integrating its DNA into the host genome. HBV integration can have several

mutagenic consequences, including large inverted duplications, deletions,

amplifications and translocation, resulting in chromosomal instability. Malignant

transformation occurs when these genetic alterations confer a selective growth

advantage to the affected cell.

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 The HBx gene has generated the most interest in HBV-related

hepatocarcinogenesis, HBx is known to be a transcription activator through its

interaction with a wide range of both viral and host regulatory elements. These

include the major histocompatibility complex, epidermal growth factor receptor, c-

myc, c-jun, c-fos, TP53, AP-1, NF-KB and SP1, among others. Through its effect on

these regulator elements, HBx can interfere with the hepatocyte DNA repair system

and the controlling elements of cellular proliferation. In addition, HBx can bind with

p53, with subsequent inhibition of p53- mediated apoptosis.

Other HBV gene elements integrating into the host genome is pre-S2/S gene,

which encodes a group of regulatory proteins called transcription activators (PreS2)

and also encodes the envelope proteins (LHBs, MHBs and SHBs). The PreS2

transcription activators undergo phosphorylation by protein kinase C, with subsequent

activation of the signalling pathways responsible for activation of transcription factors

AP-1 and NF-jB. Activation of these pathways may cause an increase in hepatocyte

proliferation. In addition, overproduction of the envelope proteins, particularly LHBs

and MHBs, may lead to over-accumulation in the cytoplasm of the hepatocytes,

causing the histological appearance of groundglass hepatocytes. This in turn may

cause cellular stress, with predisposition of the cells to undergo malignant

transformation.

Another HBV protein, known as the HBV spliced protein, is expressed in chronic

hepatitis B (CHB) infection. It has been suggested that this spliced protein can induce

apoptosis and modulate signalling via the transforming growth factor pathway, and

thus represents a novel way of promoting liver fibrosis and hepatocarcinogenesis

b. Role of HBC

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 The HCV is a positive-stranded RNA virus. The genome is organized into three

structural proteins at the N-terminal end and four functional proteins at the C-terminal

end. The structural proteins are the core (C) and envelope 1 and 2 proteins (E1 and

E2, respectively), whereas the nonstructural (NS) proteins include NS2, NS3, NS4

and NS5. HCV lacks reverse transcriptase activity, therefore HCV does not integrate

into the host genome. Because the HCV is a completely cytoplasmic-replicating virus,

the main hypothesis for HCV carcinogenesis is that it occurs via indirect pathways

through the effects of chronic inflammation and hepatocellular injury. This is likely

the major mechanism of hepatocarcinogenesis in HCV-related HCC.

The HCV core protein involved in cell signalling, transcription activation,

apoptosis, lipid metabolism and transformation. It has been shown to induce reactive

oxygen species in the absence of inflammation. The oxidative stress may decrease

metabolic processes within the mitochondria, with a decline in microsomal

triglyceride transfer protein activity, resulting in the development of steatosis. The

HCV core protein has also been shown to affect the modulation of cellular gene

products and several cellular regulatory pathways involved in cellular proliferation,

cell cycle control and tumour formation. The HCV core protein can bind to p53 and

pRb tumour suppressor proteins, modulate the expression of p21/Waf, which is

involved in cell cycle control, and interact with cytoplasmic signal transduction

molecules to regulate transcription

The E2 protein can interact with CD81, inhibit T and NK cells, thereby promoting

cell survival and proliferation. The HCV NS3 protein is a multifunctional protein with

protease, RNA helicase and NTPase activity. NS3 can promote hepatocarcinogenesis

by its interaction with certain cellular proteins, such as p21 and p53.

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 HCV NS5A, a membrane-associated protein, is involved in the replication of the

HCV genome. The intact NS5A is cytoplasmic and bound to membranes. However,

the truncated form of HCV NS5A can become localized to the nucleus to act as a

transcriptional activator. NS5A can also interact with cellular signalling components

and regulatory protein kinases, leading to the suppression of the host immune

response and inhibition of apoptosis. Therefore, an association between HCV and

HCC is likely to be a result of a combination of the independent effect of HCV on

hepatocarcinogenesis and the indirect effect of cirrhosis.

Sumber :

Fung J, Lai CL, Yuen MF. Hepatitis B and C virus-related carcinogenesis. Clin Microbiol
Infect. 2009 Nov;15(11):964-70. doi: 10.1111/j.1469-0691.2009.03035.x. PMID:
19874379.

2. Is there any big difference in prognosis and outcome in Hepatocellular Carcinoma

patient who take AFP serum biomarkers test and who doesn’t? (dr. Verina Logito)

Answer :

Postoperative biomarker response of serum AFP can be used in predicting recurrence

and survival for high-AFP HCC patients. Numerous previous studies have showed that

early recurrence is commonly associated with aggressive tumor pathological

characteristics, while late recurrence is usually associated with underlying severity of

liver disease, like cirrhosis and active hepatitis. Nevertheless, more potentially effective

predictors for early and late recurrence still need identifying to improve long-term

oncologic outcomes.

When using a serum level of 20 ng/mL as the cut-off value, sensitivity and specificity

for HCC diagnosis were 60~70% and 80~90%, respectively. When the cut-off value

increases to 400 ng/mL, the diagnostic specificity for HCC can go up to almost 100%. In

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 clinical settings, a high AFP expression (>400 ng/mL) represents a well-accepted

indicator of poor oncological characteristics of HCC, which has been demonstrated to be

closely associated with bad prognosis after various treatment modalities, including liver

transplantation, transcatheter arterial chemoembolization (TACE), and systemic therapy.

The measurement of the AFP level serum patien after HCC resection surgery could

predict the recurency dan the prognostic of HCC.

So the test of post-treatment AFP serum level as a biomarker response for malignant

tumors was important to recognized a potentially effective and readily available tool in

assessing therapeutic efficacy, predicting oncologic prognosis, as well as monitoring

postoperative recurrence.

Sumber :

Liang L, Wang MD, Zhang YM, Zhang WG, Zhang CW, Lau WY, Shen F, Pawlik TM,
Huang DS, Yang T. Association of Postoperative Biomarker Response with Recurrence
and Survival in Patients with Hepatocellular Carcinoma and High Alpha-Fetoprotein
Expressions (>400 ng/ml). J Hepatocell Carcinoma. 2021;8:103-118.
https://doi.org/10.2147/JHC.S289840

3. When the right time to measure the AFP after surgery according to the half life of

AFP? (dr. Anna Tjandrawati, SpPK(K), MKes

Answer :

AFP stands for alpha-fetoprotein. It is a protein made in the liver of a developing baby.

AFP levels are usually high when a baby is born, but fall to very low levels by the age of

1. Healthy adults should have very low levels of AFP. High levels of AFP can be a sign

of liver cancer or cancer of the ovaries or testicles, as well as noncancerous liver diseases

such as cirrhosis and hepatitis. High AFP levels don't always mean cancer, and normal

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levels don't always rule out cancer. So an AFP tumor marker test is not usually used by

itself to screen for or diagnose cancer. But it can help diagnose cancer when used with

other tests. The test may also be used to help monitor the effectiveness of cancer

treatment and to see if cancer has returned after finished the treatment.

An AFP tumor marker test may be used to: Help confirm or rule out a diagnosis of

liver cancer or cancer of the ovaries or testicles, Monitor cancer treatment. AFP levels

often go up if cancer is spreading and go down when treatment is working, See if cancer

has returned after treatment and Monitor the health of people with cirrhosis or hepatitis.

The biological Half-life of AFP in plasma is about 4 to 6 days. In Hepatocellular

Carsinoma (HCC) patients with complete surgical excision, “normal AFP Half-life was

defined as less than 7 days, and “prolonged AFP Half-life,” as any exceeding 7 days

increase the numbers of recurrency. In many journal, AFP level of 20 ng/ml was proposed

as the cut-off value for diagnosis of recurrence of HCC.

Sumber :

1. Shin WY, Suh KS, Kim T, Jeon YM, Yi NJ, Lee KU. [Could patients who underwent
hepatic resection due to hepatocellular carcinoma with high alpha-fetoprotein be
monitored for recurrence by alpha-fetoprotein level?]. Korean J Hepatol. 2010
Jun;16(2):168-75. Korean. doi: 10.3350/kjhep.2010.16.2.168. PMID: 20606501.
2. Ma, Wj., Wang, Hy. & Teng, Ls. Correlation analysis of preoperative serum alpha-
fetoprotein (AFP) level and prognosis of hepatocellular carcinoma (HCC) after
hepatectomy. World J Surg Onc 11, 212 (2013). https://doi.org/10.1186/1477-7819-
11-212