Epidemiology and Etiology of Hepatocellular carcinoma
with reference to prevalence, treatment and future
burden of HCV
Warda Mustfa*([email protected]), M.phil Zoology from university of Agriculture, Faisalabad, Punjab Pakistan
Muhammad Zubair* ([email protected]), under graduate at university of Narowal, Punjab, Pakistan
Fozan Iqbal*([email protected]), under graduate at university of Narowal, Punjab, Pakistan
Farwa masood*([email protected]) , under graduate at university of Narowal, Punjab, Pakistan
Abstract
Hepatitis is tenderness of the liver fabric. Some human beings have no sign of illness or problem since others enroot
yellow blotch of the skin and whites of the eyes, poor appetency, vomiting, tiredness, abdominal pain, or diarrhea. HCV is
one of the most ordinary blood-borne defilement. Fundamental liver cancer is the fifth most ordinary global cancer and the
third most common aagent of cancer deadliness. Hepatocellular carcinoma (HCC) accounts for between 85% and 90% of
fundamental liver cancers. Chronic hepatitis C was associated to the advancement of cirrhosis and hepatocellular
carcinoma in countless areas of the world .Eighty-seven countries announced anti-HCV predominance, while HCV
viraemic rates were accessible for fifty-four countries. Total global viraemic HCV defilement were estimated at 80 (64–
103) million infections. Globally, genotype 1 (G1) was most common (46%), displace by G3 (22%), G2 (13%), and G4
(13%). Both hepatitis B and hepatitis C is usually compassed through contaminated blood such as may occur during
needle sharing by intravenous drug users. In Pakistan more than 10 million human beings are living with Hepatitis C virus
(HCV), with high depression and deadliness. The avoidance of hepatitis C is doubtful because a vaccine to avoid HCV
defilement is not expected to be developed in the estimable future. A guarded and effective vaccine against HCV is
critically required.
Key words: HCV prevalence , HCV prevention measures, HCV diagnosis
Corresponding Authors.
1.Warda Mustafa*([email protected]), M.phil Zoology from university of Agriculture, Faisalabad, Punjab Pakistan
2.Muhammad Zubair* ([email protected]), under graduate at university of Narowal, Punjab, Pakistan
Introduction
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Hepatitis is tenderness of the liver material. The word is derivate from the Greek hêpar meaning "liver", and –itis meaning
"inflammation. It be a part to the Flaviviridae family and is a plus stranded RNA virus. ( Lindenbach BD and Rice CM. et
al. 2001)Hepatitis complete in more than a million deaths a year, for the most of part which occur obliquely from liver
scarring or liver cancer. ( Ayele, T. A. et al. 2017). Primary liver cancer, which consists predominantly of hepatocellular
carcinoma (HCC), is the fifth most common cancer worldwide and the third most common cause of cancer mortality.
Pakistan, a enroot country with 190 million citizens, thus look a high socioeconomic task of contagious diseases. (Parkin
DM. et al. 2001) In developing countries including Pakistan, the risk of HCV transmission through blood transfusion is
unknown but considered to be high due to lack of appropriate screening of blood and needs to be investigated.( Luby, S. P.
et al. 2001) The Centre for Disease Control and avoidance, USA (CDC) has stated that HBV to be 10 and 100 times more
infectious distinguished to HCV and HIV reflectively. In Pakistan, HBV infection amount is firmly increasing with an
supposed nine million people currently living with HBV. In addition ten million people are HCV infected in Pakistan.
(Chang MH, Chen CJ and Lai MS, et al. 1997)
Antibiotics may be used to amusement for chronic conditions of viral hepatitis. The World Health Organization (WHO)
has distinguished hepatitis C to a “viral time bomb” and approximate calculation that about 180 million people (some 3%
of the world’s community) are contaminated with hepatitis C virus (HCV). The predominance of hepatitis change from
country to country, and now and then it will also change among different areas of the alike country. The worldwide
hygiene of hepatitis C is well deep rooted. After all, its hygiene in Pakistan is ill-defined. (Choo QL, Kuo G, and Weiner
AJ et al. 1989)
An estimated 3% of the global population, or about 170 million persons, have been infected with hepatitis C virus (HCV).
At least 85% of infected persons become chronically infected and about 70% develop chronic hepatitis. The long-term
natural history of chronic HCV infection is not well established. Most chronically infected persons experience a slow
insidious progression of chronic liver disease, but have few, if any symptoms or physical signs of disease for decades. An
estimated 5–10% of chronically infected persons may eventually die from either cirrhosis or liver cancer.( Alter MJ,
Margolis HS and Krawczynski K et al. 1992) In nearly all populations, males have larger liver cancer degree than
females, with male: female ratios as a rule balance between 2:1 and 4:1. As of now, the largest conflict in rates (4:1) are
bring into being in midway-risk European public.(Rudolph KL and Chang S et al. 2000).
In Pakistan 10 million people are believed to be contaminated with HCV .(Umar M, Alam A and Siddiqui A, et al. 2004)
HCV was top most in Punjab (6.7%) take the place in Sindh (5.0%), Balochistan (1.5%) and Khyber Pakhtoonkhwa (1.1
%) (Chaudhary et al., 2005). Other agent contains heavy alcohol use, confident medications, toxins, other defilement,
autoimmune affection.And non-alcoholic steato hepatitis (NASH). (Bernal W and Wendon J. et al. 2013)
Chronic hepatitis C influence around 142 million human beings. In enroot countries, on account of non-discharge of
international standards concerning blood transfusion, garbage of needles for ear and nose piercing, talk over again of
syringes, injecting drug users, tattooing, cut back from barbers, unsterilized dental and usually in liquid form instruments
are the major source of the act of transporting of HCV. (Akhtar S et al. 2009) With the advent of new antivirals, boasting
improved sustained virologic response (SVR), HCV infection will be curable in nearly all patients. (Messori, Andrea,
Badiani and Brigitta et al. 2015)
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The final aim of hepatitis C cure is avoidance of hepatocellular carcinoma (HCC).The good method to make less the long-
term accident of HCC is to accomplish maintained virological response (SVR). SVR is defined as an imponderable viral
amount at 12 weeks after cure close and show a treatment. (Ryder and Stephen D.et al. 2015) At present accessible
medical care include circular and absolute acting antiviral drugs. The circular acting antivirals contain pegylated interferon
(PEG IFN) and ribavirin (RBV), which in mixture have historically been the foot of therapy for HCV. Endurance of
answer to these treatments change stand on genotype. (Neliswa A, Ming V and Wisocky,et al. 2015 )
Genotype
There are eleven different genotypes of HCV out of which six genotypes are major and classified into many sub types.
According to a study In 1997 in Pakistan 87% of individuals had genotype 3. A conference held in 2004 a panel of top 30
gastroenterologists met and reported that in Pakistan 75-90% HCV patients had genotype 3a. According to a report
published in 2006 the statistics showed that 71% patient had genotype 3 while 10% had genotype 1. These statistics are
different in 2007 showing 81% patient had genotype 3 and 9.5% had genotype 1. A more reluctant and explained report
was published in 2008 featuring 3351 patients. The results of this report showed that genotype 3a was the most prevalent
genotype in Pakistan. (Yasir waheed et al. 2009)
Prevalence
According to WHO (world health organization) the hepatitis C (HCV) is a viral time bomb because it has infected the 180
million people (3% of world’s population) out of which 130 million people might develop cirrhosis. The prevalence of
HCV varies in every country and also different in different regions of the same country. The statistics of WHO shows that
there are 350 million people that are affected with hepatitis B virus (HBV) and 170 million people with (HCV) worldwide.
The annual deaths caused by (HBV) and (HCV) are 563000 and 366000 deaths respectively. In the general population
during the period of 2000-2008 the prevalence of hepatitis C ranges from 0.4% in Karachi to 33.7% in Jarwar (Sindh). In
Multan and Islamabad the serofrequency of (HCV) is 0.3% and 12.5% respectively. In case of pregnant women the
prevalence is high ranging from 3.3% to 29.1%. The serofrequency of (HCV) in children ranged from 0.4%-36.25%. In
1996 a study in Lahore pertained that there is 4.1% prenatal transmission of (HCV) in (HCV) positive mothers. About 5%
of infants obtained HCV infection transmitted from a mother carrying both HCV antibody and HCV RNA. Every country
wants its military safe and fit so that’s why in Pakistan before induction of my recruits the screening of HCV is done and
six different studies showed a percent prevalence of 3.64% ± 0.31% in candidates for military recruitment. (Yasir waheed
et al. 2009)
Molecular basis of Hepato carcinogenesis
Hepatocarcinogenesis is strongly linked to chronic liver damage but rarely forms healthy liver during normal aging. An
explanation for this strong correlation is that development of cancer in the liver requires cell division that leads to step-
wise acquisition of genetic hits necessary for the cellular transformation. This study support this hypothesis, chemical-
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induced carcinogenesis in rodents is increased when liver cell division is induced by the partial hepatectomy (Barbason H,
Rassenfosse C and Betz EH. 1983). Most common condition linkedwith hepatocarcinogenesis is cirrhosis that forms after
long latencies (20 – 40 y) of severe liver diseases. Risk of HCC remains at lower extent during the chronic liver disease
but dramatically increases at cirrhosis stage. In order to understand the molecular basis of hepatocarcinogenesis it is
ofimportant to know the molecular mechanisms that increased liver tumor formation at cirrhosis stage. (Kawai H, et al.
2000).
Molecular Mechanisms Inducing Hepato carcinogenesis at the Cirrhosis Stage
The Liver cell progression is enhanced during chronic hepatitis, but cirrhosis is identified by reducing hepatocyte
progression.
Telomere Shortening: Limitation of Regenerative Reserve and Induction of Chromosomal Instability
Telomere hypothesis of cellular aging supportan explanation for the specific limit of regenerative reserve of liver cells.
Shortening of telomere limits the proliferationcapacity of the human cells (including hepatocytes) to a limited number of
cell divisions (Levy MZ, et al.1992).Increasedin telomere shortening of liver cells occurs during the lethal or sevreliver
disease, resulting in the storage of senescent hepatocytes at cirrhosis stage (Wiemann SU, et al. 2002). The telomere non-
functioning also activates DNA repair pathways that leadto fusions of chromosomes(Smogorzewska A, et al. 2002).
Breakage of fused chromosomes might lead to chromosomal losses andgains as well as chromosomal translocations in
daughter cells when cells with fused chromosomes enter the cell cycle (Artandi SE, Chang S, Lee SL, et al. 2000). In
support of this hypothesis it is reported that impaired hepatocyte progression induced by shortening of telomeremight
accelerate the cancer risk, a strong linked between increased p21 expression and HCC risk has been observed in human
cirrhosis(Wagayama H, et al. 2001).With the telomere shortening, aging itself effectshepatocyte progression in mice by
inducing CCAAT/ enhancer binding protein –mediated repression of E2 promoter binding factor (Iakova P, et al. 2003).
HCC Risk Factors to HBV and HCV
Gender
Males are at more risk for HCC because they have a greater chance of viral hepatitis and cirrhosis of alcohol. HCC risk
factor is still increased after controlling its factors. The higher levels of testosterone have been linked with HCC risk in the
control studies for carriers of HBV in Shanghai Taiwan (Yuan JM, 1995). HBV infection’s study showed that transgenic
mice’s androgen pathway can enhance the HBV genes transcription; androgens bind directly to the viral genome and HBV
protein HBx can enhance the androgen receptors transcription(Chiu CM, et al. 2007). The cross-sectional study indicated
the higher total levels of serum of testosterone were at the greater with risk of hepatic fibrosis and inflammation activity in
male with lethal HCV infections in the United States. While higher level of testosterone serum’slink was not examined
with HCC. (White DL, et al. 2012).
Exposure of Radiations
There are several studies that showed that there is a strong evidence of the association between the exposure of a certain
level of radiation to a population and development of chronic myeloid leukemia and acute leukemia’s. Cell will be kill
under the exposure of very high doses that are given to a limited volume of a tissue however, after cancer radiotherapy cell
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transformation and secondary leukemia is a relatively a rare event. Doses of radiations that are associated with diagnosis
procedure radiation procedures are very small and not to be linked to an increased leukemia risk (D. Rodriguez-Abreu, et
al. 2007).
Electromagnetic Fields
In the recent past, a number of reports of recent past have showed that the strong electromagnetic fields can be a risk factor
for leukemia, but other studies have failed to find these findings. Recent studies and publications showed that exposure of
electromagnetic radiations are not linked with the development of leukemia (Rodriguez-Abreu, D et al.2007).
Chemicals
Lab work and professional exposure to formaldehyde, dioxins and benzene is linked with a greater risk of leukemia
Carcinogens in tobacco smoke include benzene, polonium-210, and polycyclic aromatic hydrocarbons can cause chronic
leukemia. Estimation is done that 20% of AMLs can be linked with the cigarette smoking .(D. Rodriguez-Abreu et al.
2007).
Aflatoxin Contamination
AFB1 is a mycotoxin that is produced by Aspergillus fungus. It grows readily on food materials such as corn and peanuts
that are stored in damp and warmconditions. Exposure of AFB1 on animal experiments showed that itis a virulent
hepatocarcinogen, the International Agency for Research on Cancer to name it as carcinogenic (Yeh SH and Chen PJ.
2010).After ingestion, AFB1 is metabolized into an active intermediate, AFB1 -exo-8, 9-epoxide, that can bind with DNA
and cause damage by producing a point mutation in p53 tumor-suppressor gene p53 (Garner RC, at al. 1972). This type of
mutation has beennoticed in 30%– 60% of HCC tumors in aflatoxin-native areas.(Donato F, et al. 1998).
Exposure of Vinyl chloride
Some studies revealed that there is a strong association has been established between vinyl chloride exposure in factory
workers and angiosarcoma of liver, but not linked with other histologic liver tumors. An analysis conducted bycompiled
the results from studies of the association between occupational exposures to vinyl chloride in relation to mortality by
cancer (Wolk A, et al. 2001). Standardized Mortality Ratio for liver cancers other than angiosarcoma was 1.35 (95% CI,
1.04 –1.77) (Boffetta P, et al. 2003).
Alcohol Drinking
Ingestion of more than 50 –70 g/day of heavy intake of alcohol for longer duration, is a well-known HCC risk factor. It is
not clear that whether HCC risk is changed significantly in those withmoderate alcohol or lowalcohol intake. While heavy
ingestion of alcohol is strongly linked with the cirrhosisdevelopment, there is a little evidence of a direct carcinogenic
effect of alcohol. There is also a strong evidence for a synergistic effect of heavy alcohol intake with HBV or HCV, with
these factors operating together to enhance the HCC risk by more actively increasing cirrhosis reported that among the
alcohol drinkers, risk of HCC increased in a direct fashion with daily ingestion of more than 60 g (Donato F, et al. 2002).
It is observed that among alcohol drinkers, risk of HCC increased in a linear pattern with daily intake of alcoholgreater
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than 60 g (6 glasses of wine, or shots of hard liquor or 6 cans of beer, glasses of wine, or shots of hard liquor (Donato et
al., 2002).
Obesity
There are several studies are performed on more than 900,000 individuals in the United States and followed up for 16-year
duration, liver cancer death rates were 5 times greater among men with greatest body mass index (range, 35– 40) in
relation to those who has a normal
body mass index. (Calle EE, at al. 2003). In this same study, risk of liver cancer was not as greater in women, with a
relative risk of 1.68.There are two other population-based studies carried out from Denmark and Sweden observed
higherHCC risk (increased relative risk, 2- to 3-fold) in obese males and women compared to those who has a normal
body mass index (Moller H, et al., 1994). Abdominal obesity is strongly linked with hepatic steatosis that is due to insuln
resistance (Ratziu V, et al. 2001).
Coffee Consumption
There are several population-based studies have reported that high levels of coffee consumption (2 cups/d) with reduced
serum levels of ALT and -glutamyl transferase and reduced incidence of chronic liver disease. The consumption of high
caffeine level was linked with acute fibrosis in
patients with HCV chronic infection (Modi, A. A et al. 2011).Consumption of Coffee was also related inversely with
spread of liver disease among the participants of Hepatitis C antiviral Long-Term Treatment against Cirrhosis trial who
had hepatitis C–related cirrhosis and did not have a showed virologic response to ribavirin treatment and peg
interferon(Freedman ND, et al. 2009).
There are many epidemiologic studies have reported the effect of coffee, a reduced risk of a cirrhosisincreased a reduced
risk liver enzyme levels(Montella M, et al. 2007). Studies on animals havesuggested that coffee cause reduction in liver
carcinogenesis. Consumption of coffee also has been linked with reduction of insulin levels and risk of type 2 diabetes.
There are more than 9 epidemiologic studies carried in Southern Europe and Japan and reported on the link between coffee
intake and HCC. The coffee drinking has been linked with a reduced risk of HCC in 5 control studies (25%–75% risk
reducedwith 2– 4 cups of coffee/day as compared with control (Gallus S, et al. 2002)
Diet
Role of diet, except foraflatoxin contamination and alcohol intake in the etiology of HCC is not clear. The dietary anti-
oxidants, specially retinoic acidand selenium have been indicated to reduce liver tumors in animals. A case study of men
was conducted in Taiwan, less vegetable consumption was linked strongly with an increased HCC risk and it was only
limited to
cigarette smokers and hepatitis B virus chronic carriers (Yu MW et al J. 1995).
Levels of serum retinol were related inversely with the future risk of HCC in chronic hepatitis B carriers in that study. A
second report showed that low serum levels of selenium were also increased HCC risk (Yu MW et al . 1999)A positive
effect of high intakes of milk yogurt, white meats, eggs, and fruitshas been taken to suggested by a hospital-based case-
control study (Talamini R, et al. 2006).
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HIV
There are many studies that examined the effect of HIV infection on the proliferation of HCV-linked liver disease,
measured by fibrosis, cirrhosis, decompensated liver disease, and liver-related mortality and HCC. Effect of antiretroviral
therapy on liver disease in patients co-infected with HCV and HIV is unclear. More than 4 studies conducted and reported
that antiretroviral therapy do not link with the risk for HCC, however, it is very difficult to make conclusions because of
a smaller number of studies on HCC. Antiretroviral therapy might reduce the risk for HCC risk might be reduced by
antiretroviral therapy, providing link between HIV infection and increased liver disease.31 HBV infection of HBV persists
in 25% of HIV-infected adults, in relation to less than 5% of adults having no HIV infection. Individuals infected with
HBV and HIV has a greater risk for liver-related death(Westin J, et al. 2002).
Wnt/-catenin
Catenin pathway is regulated strongly during early liver development (Micsenyi A, et al. 2004).The activation of the
catenin pathway commonly occurs inhuman HCC involving somatic mutations and mic (Mobasheri, Aet al. 1998)as well
asnegative regulatorstranscriptional repression of (Chan DW, et al. 2006). And the c-met proto-oncogene/hepatocyte
growth factor receptor (MET) pathway (Kaposi-Novak Activation of developmental pathways reportedthat some HCC
may arose from stem cells of liver. The normal regeneration of liver does not have any need of stem cells because the
somatic hepatocytes possess the ability to re-enter into the cell cycle. Growth-inhibitory environment in cirrhotic liver may
cause an activation and transformation of stem cells in liver. Very first studies have investigated the evidence for the
occurrence of stem cell populations in human HCC (Chiba T, et al. 2006) and an expression of gene of stem cells of
human HCC (Lee JS, et al. 2006).
PI3K/ Akt.
The Akt activation signaling and effected expression of tension homolog phosphatase and phosphatase(are negative
Aktregulator) have been investigatedin 40%–60% of human HCC (Hu TH, et al. 2003). Correlation between activation of
myc and tumor prognosis has been investgated(Wang Y, et al. 2006).One mechanism of activation of myc in human HCC
is the amplification locus of the chromosome, 178 that might be induced by the telomere non-functioning and the
dysfunctional checkpoints. An increased copy of mouse chromosome 15 (carrying the myc-gene locus) is a common
abnormality in murine HCC induced in extent of p53 mutation and the shortening of telomereCell(Lechel A, et al.
2007).Due to the similarities in and human HCC and mouse, theinterspecies comparison will be a beneficial tool for more
identification of oncogenes and tumor inhibitorsrelated to the human hepatocarcinogenesis (Zender L, et al. 2006).
Immortality of Tumor cells
Greater than 90% of human HCC indicated an activation of telomerase, and the up-regulation of telomerase reverse
transcriptase is a significant indicator of human HCC carcinoma (Llovet JM, et al. 2006)The telomerase can synthesize by
telomeres de novo and expression of telomerase reverse transcriptase is the controlling step for the activation of
telomerase activation and immortalization of the human cells. Studiesonhuman cells have investigated that the telomerase
is an important component to transformed human cells with a specific limit of progressive potential. In a normal human
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telomerase is inactive liver but the activation occurs during transition of pre-malignant lesions to HCC (Luedde T, et al.
2007).
Hygiene of HCV transmission
Hepatitis C virus is greater fluently broadcast by direct percutaneous exposure to contamination blood, such as through
blood transfusion from contamination donors and giving of contaminated accessories among injecting drug consumers .(
Mansell CJ. Et al.1995) Haemodialysis patients and healthcare workers who are apparent to needle stick injuries in a
career setting are also at risk from uncovering to infectious blood, as are baby born to infected women. In addition, HCV
can be communicated by sexual or domestic exposure to a contaminated contact; however, the efficiency of transposal in
these settings appears to be short.
Despite an common popularity of HCV infection of 4–5% has been found among family and sex contacts of infected guy
in a number of analysis, most of these analysis were preside over in countries where transmission of HCV infection may
be affiliate with common display to contaminated accessories used in acceptable and non acceptable medical agenda in the
past . ( Alter MJ et al. 1998) There are still huge break in our understanding of the al round epidemiology of HCV.
The comparative addition of the various sources of infection has infrequently been investigated in population-based
epidemiological studies in most terrestrial areas. In addition, many ignored questions are living about the roles of risk
factors and way of life circumstances that may be linked with HCV spread in different areas of the world. Epidemiological
studies on the act of inherent risk factors, such as medical processes, injections for medications and booster dose,
injections used outside of medical background, tattooing, and incision methods, have shown wide terrestrial variations
with basic implications for local populations and inherent prevention and control programmes. As HCV can be sexually
send (although not often between healthy persons), the role of co infection with other sexually communicated diseases,
such as HIV/AIDS, need to be additional studied, specifically for those that can result in open genital rash, such as
gonorrhea infection, scabies and herps. (D. Lavanchy et al. 2010)
Diagnosis
The patients (atleast 70 percent) with infection of HCV are non-symptomatic, but when signs do occur, they are not
specific and include weakness, weight loss fatigue, myalgias, arthralgias nausea and anorexia (Wasley et al. 2008: Koff,
R.S.1981).). Laboratory tests or symptoms of cirrhosis should prompt HCV antibody testing, that followed by
confirmatory tests (Chou R et al. 2004).SevreHCV infection caused to cirrhosis in almost 10 to 20 percent patients, by
increasing the risk of chronic liver disease complications, also including hypertension, hemorrhage, ascites and
hepatocellular carcinoma (Chou R et al., 2004: Jou JH et al. 2008).
Diagnostic tests for the detection of HCV infection
The diagnostic test used for HCV infection detection isthe recombinant immunoblotassay, HCV antibody enzyme
immunoassay and quantitative HCV RNA polymerase chain reaction (PCR). The common diagnostic tests are listed in
Table 2 (Ghany MG et al. 2009;) Most commonly used assay for HCV detection antibodies is the immunoassay of
enzyme. Positive enzyme immunoassay must be used by a confirmatory test. It gives false positive results when it is used
in the low-risk groups (González V, et al. 2008). For HCV antibody detection a saliva-based test may be available soon.
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The Recombinant immunoblot assay that is a confimatory test for immunoassay of enzyme, sense antibodies to individual
antigens of HCV. (Scott JD and Gretch DR. 2007).
Laboratory Test
There are two classes of assays that are used in the detection and management for HCVinfection: The serologic assay
sense the specific antibody to hepatitis C virus (anti-HCV) and the molecular assays detect the nucleic acid of virus. Both
of these have no role in the estimation of severity of the disease or its progression (Ghany, M. Get al. 2009).
Serologic Assays
The tests that detect anti-HCV are used both to detect and screen HCV infection. Anti-HCV can be detected in theplasma
or serum by using a number of immunoassays. There are two enzyme immunoassays (EIAs) are recommended by the U.S.
Food and Drug Administration (FDA) for clinical use, HCV Version 3.0 ELISA (Ortho-Clinical Diagnostics, Raritan, NJ),
Abbott HCV EIA 2.0 (Abbott Laboratories, Abbott Park, IL) and as well as one enhanced chemiluminescence
immunoassay (CIA) VITROS Anti-HCV assay, (Ortho-Clinical Diagnostics, Specificity of recent EIAs for anti-HCV is
higher than 99% (Colin C, at al. 2001).
Molecular Assays
Qualitative assays have been more efficient than quantitative assays. There is no need for the qualitative assay due to the
availability of transcription-mediated amplification(TMA) assays and real time polymerase chain reaction (PCR)- based assays
with the sensitivity of 10-50 IU/mL (Stramer SL, et al. 2000; Scott JD and Gretch DR. 2007). The highly detectable assay with
this lesser detection limit is considered appropriate for therapy during monitoring., With the specificity range of 98% to 99%, all
the easily available assays have excellent., The World Health Organization in 1997 formed the first International standard for
HCV RNA nucleic acid technology (Saldanha J, et al. 1999)and IU rather than copies of virus is now most commonly used unit
to find test results (Pawlotsky JM, et al. 2000).
Utility of the Liver Biopsy and Noninvasive
Tests of Fibrosis
Three main reasons for doing a liver biopsy: it gives beneficial information on the current status of liver injury, it detect the features that are
useful in the decision for therapy and it can be showed severe fibrosis or cirrhosis that is necessary for hepatocellular carcinoma (HCC) and
viruses screening. Liver biopsy is performed for stage and grade of the liver injury, but it also gives information on other histopathological
features that may have facing proliferation of liver disease (Kleiner DE. 2005). Grade defines the limit of necro-inflammatory activity, while the
stage marked the limit of fibrosis or the occurrence of cirrhosis. There are many scoring systems have been recieved, the most common being the
French METAVIR, the Batts-Ludwig, the International Association for the Study of the Liver (IASL) and the Ishak Scoring systems (Scheuer PJ.
1991)
Signs and Symptoms
The symptoms of hepatitis C tend to be intermittent, mild and non specific. The most common symptom of chronic
hepatitis C is fatigue which can be described as lethargy, malaise, lack of stamina and the patient’s fatiguability rate is
high. The other symptoms which are less frequent include feverishness, nausea, weight loss, muscle aches and poor
appetite. There is a decrease in the quality of life of patient because these symptoms are rarely incapacitating. The severity
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of disease depends upon the symptoms. The asymptomatic person has less severe disease than symptomatic. Due to non
specificity of the symptoms of HCV it is very difficult to define what percentage of people were symptomatic but it is
always less than 25%. According to a study in which 108 patients participated 70% had one or more of six symptoms
(fatigue, nausea, abdominal pain, anorexia, itching and dark urine). 62% patients showed a most common symptom which
was fatigue. Other symptoms such as abdominal pain, itching and dark urine were also significantly present but in a
minority of patients ( Hoofnagle 1997).
Treatment
Sustained virologic response is the delegate counter used by most studies to assess the effectiveness of therapy and is
correlate with bettered outcomes, such as low likelihood of viral relapse, reduced mortality, and reduced exposure of
cirrhosis and hepatocellular carcinoma.(Mangia A, Minerva N and Bacca D, et al. 2008). All persons with chronic HCV
infection should be examined applicant for treatment; however, several factors power the decision to continue with
therapy. Treatment for HCV infection is widely acknowledged in persons at least 18 years of age who are consenting to be
treated and to conform to treatment necessity, with abnormal serum alanine transaminase (ALT) principles, denoting liver
fibrosis or committed cirrhosis, and normal renal function, and without anemia or neutropenia. Before starting therapy,
diagnostic blood work should be achieved, including a complete blood count, complete metabolic board, and measurement
of thyroid-stimulating hormone level, because interferon therapy is affiliated with leukopenia, thrombocytopenia, and
autoimmune thyroiditis. Human being with chronic HCV infection and anemia, renal deficiency, autoimmune hepatitis,
de compensated cirrhosis, pregnancy, caustic cardiopulmonary disease, unrestrained major abasement, or unrestrained
hyperthyroidism are not good applicant for treatment.(Strader DB, Wright T and Thomas DL et al. 2004)
Blood urea nitrogen and serum creatinine levels should be assess because ribavirin (Rebetol) is renally discharged and
should be used with carefulness in patients with renal efficiency. (Koff RS et al. 2008) Genotype assimilation aid in
predicting reaction to treatment because persons with genotype 1 have lower degree of reaction to therapy than patients
with genotypes 2 and liver biopsy to determine disease cruelty may be thought out when determining whether to initiate
treatment in patients with chronic HCV infection and actively normal transaminase levels or with relative conflict to
therapy, or for predictive purposes (e.g., in patients with genotype 1). (Scott JD et al. 2007)
Options Treatment
Approved therapy for the treatment of chronic HCV contamination is pegylated interferon and ribavirin.,38(Mc Hutchison
JG et al. 2001) Oral ribavirin monotherapy is not productive for encourage sustained virologic response (relative risk =
1.01; 95% confidence interval, 0.96 to 1.07).(Brok J et al. 2009)
There are two conceptions of pegylated interferon that arecertified for HCV therapy: pegylated interferon alfa-2a
(Pegasys) and pegylated interferon alfa-2b (Pegintron). Sustained virologic response ratio for pegylated interferon
monotherapy and pegylated interferon plus ribavirin is 25 to 39 percent and 54 to 60 percent,The assessable HCV RNA
level is used to evaluate response to therapy and as a adviser to blow off treatment. A negative viral charge test after four
weeks of therapy is divining of sustained virologic response. (Ghany MG and Strader DB et al. 2009)
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Opposite to failure to accomplish a 100-fold reduction in viral load by week 12 of therapy has a strong negative predictive
value for sustained virologic response and convey advice that treatment is likely useless and should be blocked. (Schade,
R. R. 2010)
Medical care
In contrast to hepatitis A and B, advancement to chronic hepatitis C is plenty greater common. The conclusive object of
hepatitis C treatment is blockage of hepatocellular carcinoma (HCC).The good action to decrease the long-term risk of
HCC is to accomplish sustained virological response (SVR).(Messori and Andrea et al. 2015) SVR is defined as an
imponderable viral load at 12 weeks after cure close and display cure.At present available treatments involve indirect and
direct acting antiviral drugs. The indirect acting anti virals involve pegylated interferon (PEG IFN) and ribavirin (RBV),
which in mixture have historically been the support of therapy for HCV. Continuation and reaction to these treatments
alter based on genotype. (Stephen D et al. 2015)
Genotype 1 (GT1), which is the most prevalent genotype in the United States and around the world, can now be cured with
a direct acting antiviral regimen. (Raymond T et al. 2015) The American Association for the Study of Liver Diseases and
the Infectious Diseases Society of America (AASLD-IDSA) advise antiviral treatment for all patients with chronic
hepatitis C infection other than for those with extra chronic medical circumstances that brink their life assurance.
(Guidance Panel et al. 2015).
Strategies to prevent and control hepatitis C
Scope to avert and mastery hepatitis C is confined. The addition of a vaccine is not likely in the account able future, and
immune globulin is not active for post-exposure prophylaxis. At present available prevention measures involve primary
prevention activities that decrease the risk of flattering contaminated with HCV and secondary prevention activities that
decrease the chance taken for chronic disease in HCV-contaminated creature.( Locarnini SA et al. 1995)
Primary prevention
From a worldwide perspective, the greatest impact on the disease stress affiliated with HCV contamination will likely be
accomplished by focusing exertion on primary prevention. Primary prevention action can reduce or remove the risk of
transposable from
(1) No socomial exposures, involve transfusion of blood and blood amount, and other percutaneous exposures to blood
such as through use of unsterile medical and dental accessories and un intensional needle sticks
(2) Giant risk practices (e.g. injecting drug use, unprotected sex with multiple partners).
The primary methods to prevent HCV transmission from blood and blood products are absolute of donors who are
appreciate to be at increased risk of germs by history or who have serologic markers of HCV communicability.
Extraneous, plasma derivatives (e.g. clotting factor concentrates, immune globulin) should either abide viral calm or be
HCV RNA negative by polymerase chain reaction. Conveyance of HCV connect in mind with high-risk practices (e.g.
injecting drug use, defenseless sex with multiple colleague) can be prevented by analyze and adminish persons with a
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history these convention and by educational work to prevent beginning of these conventions. Educational struggle to
prevent beginning of drug injection are particularly important for children and pre adult or immature because HCV
infection is very quickly accomplished after beginning of injecting drug employment. (E.E. Mast et al. 1999)
Secondary prevention
Secondary prevention activities make less the danger for chronic disease by recognize HCV-infected persons through
demonstrative testing and by providing applicable medical administration and antiviral therapy. In appropriate, counseling
of HCV infected persons to reduce or avoid from alcohol consumption may prevent disease advancement. Antiviral
treatment is also accessible, and treatment direction has been matured. Nevertheless, treatment is expensive and outside
limits the resources accessible in many countries. Additionally, the benefits of early discovery and treatment of persons
with asymptomatic infection have not been clearly settled, a high relative amount of persons do not act in response to at
present available treatment, and the long-term benefit of treatment has not been driven.( E.E. Mast et al. 1999)
Future Burden of HBV- and HCV-Related HCC
Among the United States, incidence of HBV-linkedHCC is likely to remain steady. Even vaccinationsagainst the HBV
could prevent HCC; it does not stopcancer in persons with severe or chronic infections. Most recent (1999–2006).
National Health and Nutrition Examination Survey noticed that only 0.27% of US population, 6 years or older, had severe
or chronic HBV infection (Bugianesi E, et al. 2004). National Health and Nutrition Examination Survey also reported that
1.3% of civilian US population had severe or chronic HCV infection; at least 66% of those infected were born between
1945 and 1964, and have been living with this disease for several decades. This study was also related to many risk
factors for proliferation, such as alcohol consumption and the obesity. A report estimated that almost 50% of individuals
with lethal HCV infections in United States are not diagnosed. Studies suggested that, without the effective treatment, total
number of patients with HCC or cirrhosis will be double in 2020 (El Serag HB. 2004).
The World Health Organization data showed that a massive increase in the all of the people diagnosed with primary liver
cancer, massively HCC, from 437,408 cases in 1990 to 714,600 in 2002 (Adami HO, Chow WH, Nyren O, et al.
1996)Percentage of HCC infection linked with HBV has reduced speedily while percentage linked with HCV has been
greater. So, after reviewing literature we can say that each country or region country might be has its own case study. The
World Health Organization death data from many European countries showed that between 1980 and 2004, total mortality
by HCC among males increased inGermany, and Switzerland andAustria, while it reduced to a greater extent inItaly
France and Italy (Wideroff L and Schottenfeld, D. 2006). In 2010 The Institute of Medicine study onLiver Cancer and
Hepatitis marked the awareness inability about HCV and HBV infections and lesser understanding and knowledge about
the limit and effective loss of their public health impact. HCV- and HBV-linked HCC can be prohibited by increasing the
screening and diagnosis of patients, by various approaches such as vaccination of juvenile and adults susceptibility
against HBV, a flatoxin exposure reduction, treating the infected patients with severe HCV and HBV infections, co-
factors reducing for proliferation (metabolic syndrome and alcohol drinking ) at the early stage diagnosis and treatment.
References
IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151
102
Copyright © 2019 IEEE-SEM Publications
Gogela, N. A., Lin, M. V., Wisocky, J. L., & Chung, R. T. (2015). Enhancing our understanding of current therapies for hepatitis C virus
(HCV). Current HIV/AIDS Reports, 12(1), 68-78.
Zimmerman, J. J., Akhtar, S. R., Caldwell, E., & Rubenfeld, G. D. (2009). Incidence and outcomes of pediatric acute lung
injury. Pediatrics, 124(1), 87-95.
Bernal, W., & Wendon, J. (2013). Acute liver failure. New England Journal of Medicine, 369(26), 2525-2534.
Bari, A., Akhtar, S., Rahbar, M. H., & Luby, S. P. (2001). Risk factors for hepatitis C virus infection in male adults in Rawalpindi–Islamabad,
Pakistan. Tropical medicine & international health, 6(9), 732-738.
Shukla, R., Bansal, V., Chaudhary, M., Basu, A., Bhonde, R. R., & Sastry, M. (2005). Biocompatibility of gold nanoparticles and their
endocytotic fate inside the cellular compartment: a microscopic overview. Langmuir, 21(23), 10644-10654.
Hamid, S., Umar, M., Alam, A., Siddiqui, A., Qureshi, H., & Butt, J. (2004). PSG consensus statement on management of hepatitis C virus
infection--2003. JPMA. The Journal of the Pakistan Medical Association, 54(3), 146.
Rudolph, K. L., Chang, S., Millard, M., Schreiber-Agus, N., & DePinho, R. A. (2000). Inhibition of experimental liver cirrhosis in mice by
telomerase gene delivery. Science, 287(5456), 1253-1258.
Alter, M. J., Margolis, H. S., Krawczynski, K., Judson, F. N., Mares, A., Alexander, W. J., ... & Meeks, E. L. (1992). The natural history of
community-acquired hepatitis C in the United States. New England journal of medicine, 327(27), 1899-1905.
Choo, Q. L., Kuo, G., Weiner, A. J., Overby, L. R., Bradley, D. W., & Houghton, M. (1989). Isolation of a cDNA clone derived from a blood-
borne non-A, non-B viral hepatitis genome. Science, 244(4902), 359-362.
Lindenbach, B. D., & Rice, C. M. (2001). Flaviviridae: the viruses and their replication, vol. 1.
Akinyemiju, T., Abera, S., Ahmed, M., Alam, N., Alemayohu, M. A., Allen, C., ... & Ayele, T. A. (2017). The burden of primary liver cancer and
underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015. JAMA
oncology, 3(12), 1683-1691.
Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2001). Estimating the world cancer burden: Globocan 2000. International journal of
cancer, 94(2), 153-156.
Chang, M. H., Chen, C. J., Lai, M. S., Hsu, H. M., Wu, T. C., Kong, M. S., ... & Chen, D. S. (1997). Universal hepatitis B vaccination in Taiwan
and the incidence of hepatocellular carcinoma in children. New England Journal of Medicine, 336(26), 1855-1859.
Choo, Q. L., Kuo, G., Weiner, A. J., Overby, L. R., Bradley, D. W., & Houghton, M. (1989). Isolation of a cDNA clone derived from a blood-
borne non-A, non-B viral hepatitis genome. Science, 244(4902), 359-362. Adami, H. O., Chow, W. H., Nyrén, O., Berne, C., Linet, M. S.,
Ekbom, A., ... & Fraumeni, J. F. (1996). Excess risk of primary liver cancer in patients with diabetes mellitus. JNCI: Journal of the National
Cancer Institute, 88(20), 1472-1477.
Anderson, D., Bishop, J. B., Garner, R. C., Ostrosky-Wegman, P., & Selby, P. B. (1995). Cyclophosphamide: review of its mutagenicity for an
assessment of potential germ cell risks. Mutation research/fundamental and molecular mechanisms of mutagenesis, 330(1-2), 115-181.
Artandi, S. E., Chang, S., Lee, S. L., Alson, S., Gottlieb, G. J., Chin, L., & DePinho, R. A. (2000). Telomere dysfunction promotes non-reciprocal
translocations and epithelial cancers in mice. Nature, 406(6796), 641.
Barbason, H., Rassenfosse, C., & Betz, E. H. (1983). Promotion mechanism of phenobarbital and partial hepatectomy in DENA
hepatocarcinogenesis cell kinetics effect. British journal of cancer, 47(4), 517.
Boffetta., Brennan, P., Gajalakshmi, V., Mathew, A., Shanta, V., Varghese, C., & Znaor, A.,. (2003). Independent and combined effects of
tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. International journal of
cancer, 105(5), 681-686.
Bugianesi, E., Manzini, P., D'Antico, S., Vanni, E., Longo, F., Leone, N., ... & Rizzetto, M. (2004). Relative contribution of iron burden, HFE
mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology, 39(1), 179-187.
Calle, E. E., Rodriguez, C., Walker-Thurmond, K., & Thun, M. J. (2003). Overweight, obesity, and mortality from cancer in a prospectively
studied cohort of US adults. New England Journal of Medicine, 348(17), 1625-1638.
IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151
103
Copyright © 2019 IEEE-SEM Publications
Chiba, T., Kita, K., Zheng, Y. W., Yokosuka, O., Saisho, H., Iwama, A., ... & Taniguchi, H. (2006). Side population purified from hepatocellular
carcinoma cells harbors cancer stem cell–like properties. Hepatology, 44(1), 240-251.
Chiu, C. M., Chiu, C. S., & Chang, H. C. (2007). Examining the integrated influence of fairness and quality on learners’ satisfaction and
Web‐ based learning continuance intention. Information systems journal, 17(3), 271-287.
Cho, L. Y., Yang, J. J., Ko, K. P., Park, B., Shin, A., Lim, M. K., & Yoo, K. Y. (2011). Coinfection of hepatitis B and C viruses and risk of
hepatocellular carcinoma: systematic review and meta‐ analysis. International journal of cancer, 128(1), 176-184.
Colnot, S., Decaens, T., Niwa-Kawakita, M., Godard, C., Hamard, G., Kahn, A., ... & Perret, C. (2004). Liver-targeted disruption of Apc in mice
activates β-catenin signaling and leads to hepatocellular carcinomas. Proceedings of the National Academy of Sciences, 101(49), 17216-17221.
di Fagagna, F. D. A., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., ... & Jackson, S. P. (2003). A DNA damage
checkpoint response in telomere-initiated senescence. Nature, 426(6963), 194.
Djojosubroto, M. W., Chin, A. C., Go, N., Schaetzlein, S., Manns, M. P., Gryaznov, S., ... & Rudolph, K. L. (2005). Telomerase antagonists
GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology, 42(5), 1127-1136.
Donato, F., Boffetta, P., & Puoti, M. (1998). A meta‐ analysis of epidemiological studies on the combined effect of hepatitis B and C virus
infections in causing hepatocellular carcinoma. International journal of cancer, 75(3), 347-354.
El-Serag, H. B. (2004). Hepatocellular carcinoma: recent trends in the United States. Gastroenterology, 127(5), S27-S34.
Farazi, P. A., Glickman, J., Jiang, S., Yu, A., Rudolph, K. L., & DePinho, R. A. (2003). Differential impact of telomere dysfunction on initiation
and progression of hepatocellular carcinoma. Cancer research, 63(16), 5021-5027.
Feld, J. J., Modi, A. A., El–Diwany, R., Rotman, Y., Thomas, E., Ahlenstiel, G., ... & Ghany, M. G. (2011). S-adenosyl methionine improves
early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders. Gastroenterology, 140(3), 830-839.
Fiore, G., Fera, G., Napoli, N., Vella, F., & Schiraldi, O. (1996). Liver steatosis and chronic hepatitis C: a spurious association?. European
journal of gastroenterology & hepatology, 8(2), 125-129.
Freedman, N. D., Everhart, J. E., Lindsay, K. L., Ghany, M. G., Curto, T. M., Shiffman, M. L., ... & Hoefs, J. C. (2009). Coffee intake is
associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology, 50(5), 1360-1369.
Gallus, S., Colombo, P., Scarpino, V., Zuccaro, P., Apolone, G., & La Vecchia, C. (2002). Smoking in Italy, 2002. Tumori Journal, 88(6), 453-
456.
He, X. C., Yin, T., Grindley, J. C., Tian, Q., Sato, T., Tao, W. A., ... & Wiedemann, L. M. (2007). PTEN-deficient intestinal stem cells initiate
intestinal polyposis. Nature genetics, 39(2), 189.
Hu, T. H., Huang, C. C., Lin, P. R., Chang, H. W., Ger, L. P., Lin, Y. W., ... & Tai, M. H. (2003). Expression and prognostic role of tumor
suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer: Interdisciplinary International Journal of the American Cancer
Society, 97(8), 1929-1940.
Hwang, S. J., Bellocq, N. C., & Davis, M. E. (2001). Effects of structure of β-cyclodextrin-containing polymers on gene delivery. Bioconjugate
chemistry, 12(2), 280-290.
Iakova, P., Awad, S. S., & Timchenko, N. A. (2003). Aging reduces proliferative capacities of liver by switching pathways of C/EBPα growth
arrest. Cell, 113(4), 495-506.
Ikeda, K., Saitoh, S., Suzuki, Y., Kobayashi, M., Tsubota, A., Koida, I., ... & Kumada, H. (1998). Disease progression and hepatocellular
carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. Journal of hepatology, 28(6), 930-938.
Jee, S. H., Ohrr, H., Sull, J. W., & Samet, J. M. (2004). Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in
Korea. Journal of the national cancer institute, 96(24), 1851-1856.
Kanwal, F., Hoang, T., Kramer, J. R., Asch, S. M., Goetz, M. B., Zeringue, A., ... & El–Serag, H. B. (2011). Increasing prevalence of HCC and
cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology, 140(4), 1182-1188.
Kawai, H., Imanaga, S., & Kobayashi, T. (2000). U.S. Patent No. 6,064,082. Washington, DC: U.S. Patent and Trademark Office.
IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151
104
Copyright © 2019 IEEE-SEM Publications
Kurozawa, Y., Ogimoto, I., Shibata, A., Nose, T., Yoshimura, T., Suzuki, H., ... & Tamakoshi, A. (2005). Coffee and risk of death from
hepatocellular carcinoma in a large cohort study in Japan. British journal of cancer, 93(5), 607.
Lechel, A., Holstege, H., Begus, Y., Schienke, A., Kamino, K., Lehmann, U., ... & Rudolph, K. L. (2007). Telomerase deletion limits progression
of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology, 132(4), 1465-1475.
Levy, M. Z., Allsopp, R. C., Futcher, A. B., Greider, C. W., & Harley, C. B. (1992). Telomere end-replication problem and cell aging. Journal of
molecular biology, 225(4), 951-960.
Luedde, T., Beraza, N., Kotsikoris, V., van Loo, G., Nenci, A., De Vos, R., ... & Pasparakis, M. (2007). Deletion of NEMO/IKKγ in liver
parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer cell, 11(2), 119-132.
Micsenyi, A., Tan, X., Sneddon, T., Luo, J. H., Michalopoulos, G. K., & Monga, S. P. (2004). β-Catenin is temporally regulated during normal
liver development. Gastroenterology, 126(4), 1134-1146.
Møller, H., Mellemgaard, A., Lindvig, K., & Olsen, J. H. (1994). Obesity and cancer risk: a Danish record-linkage study. European journal of
cancer, 30(3), 344-350.
Montella, M., Polesel, J., La Vecchia, C., Maso, L. D., Crispo, A., Crovatto, M., ... & Franceschi, S. (2007). Coffee and tea consumption and risk
of hepatocellular carcinoma in Italy. International journal of cancer, 120(7), 1555-1559.
Plentz, R. R., Park, Y. N., Lechel, A., Kim, H., Nellessen, F., Langkopf, B. H. E., ... & Roncalli, M. (2007). Telomere shortening and inactivation
of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology, 45(4), 968-976.
Poynard, T., Yuen, M. F., Ratzin, V., & Lai, C. L. (2003). Viral hepatitis C. The Lancet, 362(9401), 2095-2100.
Ratziu, V., Bonyhay, L., Di Martino, V., Charlotte, F., Cavallaro, L., Sayegh‐ Tainturier, M. H., .. & Poynard, T. (2002). Survival, liver failure,
and hepatocellular carcinoma in obesity‐ related cryptogenic cirrhosis. Hepatology, 35(6), 1485-1493.
Rodriguez-Abreu, D., Bordoni, A., & Zucca, E. (2007). Epidemiology of hematological malignancies. Annals of oncology, 18(suppl_1), i3-i8.
Rubbia-Brandt, L., Quadri, R., Abid, K., Giostra, E., Malé, P. J., Mentha, G., ... & Negro, F. (2000). Hepatocyte steatosis is a cytopathic effect of
hepatitis C virus genotype 3. Journal of hepatology, 33(1), 106-115.
Satyanarayana, L., Reddy, K. M., & Manorama, S. V. (2003). Nanosized spinel NiFe2O4: a novel material for the detection of liquefied
petroleum gas in air. Materials Chemistry and Physics, 82(1), 21-26.
Shachaf, C. M., Kopelman, A. M., Arvanitis, C., Karlsson, Å., Beer, S., Mandl, S., ... & Yang, Q. (2004). MYC inactivation uncovers pluripotent
differentiation and tumour dormancy in hepatocellular cancer. Nature, 431(7012), 1112..
Shimazu, T., Inoue, I., Araki, N., Asano, Y., Sawada, M., Furuya, D., ... & Greenberg, J. H. (2005). A peroxisome proliferator-activated receptor-
γ agonist reduces infarct size in transient but not in permanent ischemia. Stroke, 36(2), 353-359.
Sicklick, J. K., Li, Y. X., Melhem, A., Schmelzer, E., Zdanowicz, M., Huang, J., ... & Reid, L. M. (2006). Hedgehog signaling maintains resident
hepatic progenitors throughout life. American Journal of Physiology-Gastrointestinal and Liver Physiology, 290(5), G859-G870.
Smogorzewska, A., & de Lange, T. (2002). Different telomere damage signaling pathways in human and mouse cells. The EMBO
journal, 21(16), 4338-4348.
Talamini, R., Polesel, J., Montella, M., Maso, L. D., Crispo, A., Tommasi, L. G., ... & Franceschi, S. (2006). Food groups and risk of
hepatocellular carcinoma: a multicenter case‐ control study in Italy. International journal of cancer, 119(12), 2916-2921.
V., Wolk, Pisani, P., Tenet, A Bergström, A.., & Adami, H. O. (2001). Overweight as an avoidable cause of cancer in Europe. International
journal of cancer, 91(3), 421-430.
Wagayama, H., Shiraki, K., Yamanaka, T., Sugimoto, K., Ito, T., Fujikawa, K., ... & Nakano, T. (2001). p21WAF1/CTP1 expression and
hepatitis virus type. Digestive diseases and sciences, 46(10), 2074-2079.
Wang, Y., & Zhang, Q. (2006). Are American children and adolescents of low socioeconomic status at increased risk of obesity? Changes in the
association between overweight and family income between 1971 and 2002. The American journal of clinical nutrition, 84(4), 707-716.
IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151
105
Copyright © 2019 IEEE-SEM Publications
Westin, J., Nordlinder, H., Lagging, M., Norkrans, G., & Wejstål, R. (2002). Steatosis accelerates fibrosis development over time in hepatitis C
virus genotype 3 infected patients. Journal of hepatology, 37(6), 837-842.
White, D. L., Thrift, A. P., Kanwal, F., Davila, J., & El-Serag, H. B. (2017). Incidence of hepatocellular carcinoma in all 50 United States, from
2000 through 2012. Gastroenterology, 152(4), 812-820.
Adami, H. O., Chow, W. H., Nyrén, O., Berne, C., Linet, M. S., Ekbom, A., ... & Fraumeni, J. F. (1996). Excess risk of primary liver cancer in
patients with diabetes mellitus. JNCI: Journal of the National Cancer Institute, 88(20), 1472-1477.
Anderson, D., Bishop, J. B., Garner, R. C., Ostrosky-Wegman, P., & Selby, P. B. (1995). Cyclophosphamide: review of its mutagenicity for an
assessment of potential germ cell risks. Mutation research/fundamental and molecular mechanisms of mutagenesis, 330(1-2), 115-181.
Artandi, S. E., Chang, S., Lee, S. L., Alson, S., Gottlieb, G. J., Chin, L., & DePinho, R. A. (2000). Telomere dysfunction promotes non-reciprocal
translocations and epithelial cancers in mice. Nature, 406(6796), 641.
Barbason, H., Rassenfosse, C., & Betz, E. H. (1983). Promotion mechanism of phenobarbital and partial hepatectomy in DENA
hepatocarcinogenesis cell kinetics effect. British journal of cancer, 47(4), 517.
Boffetta., Brennan, P., Gajalakshmi, V., Mathew, A., Shanta, V., Varghese, C., & Znaor, A.,. (2003). Independent and combined effects of
tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. International journal of
cancer, 105(5), 681-686.
Bugianesi, E., Manzini, P., D'Antico, S., Vanni, E., Longo, F., Leone, N., ... & Rizzetto, M. (2004). Relative contribution of iron burden, HFE
mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Hepatology, 39(1), 179-187.
Calle, E. E., Rodriguez, C., Walker-Thurmond, K., & Thun, M. J. (2003). Overweight, obesity, and mortality from cancer in a prospectively
studied cohort of US adults. New England Journal of Medicine, 348(17), 1625-1638.
Chiba, T., Kita, K., Zheng, Y. W., Yokosuka, O., Saisho, H., Iwama, A., ... & Taniguchi, H. (2006). Side population purified from hepatocellular
carcinoma cells harbors cancer stem cell–like properties. Hepatology, 44(1), 240-251.
Chiu, C. M., Chiu, C. S., & Chang, H. C. (2007). Examining the integrated influence of fairness and quality on learners’ satisfaction and
Web‐ based learning continuance intention. Information systems journal, 17(3), 271-287.
Colnot, S., Decaens, T., Niwa-Kawakita, M., Godard, C., Hamard, G., Kahn, A., ... & Perret, C. (2004). Liver-targeted disruption of Apc in mice
activates β-catenin signaling and leads to hepatocellular carcinomas. Proceedings of the National Academy of Sciences, 101(49), 17216-17221.
di Fagagna, F. D. A., Reaper, P. M., Clay-Farrace, L., Fiegler, H., Carr, P., von Zglinicki, T., ... & Jackson, S. P. (2003). A DNA damage
checkpoint response in telomere-initiated senescence. Nature, 426(6963), 194.
Djojosubroto, M. W., Chin, A. C., Go, N., Schaetzlein, S., Manns, M. P., Gryaznov, S., ... & Rudolph, K. L. (2005). Telomerase antagonists
GRN163 and GRN163L inhibit tumor growth and increase chemosensitivity of human hepatoma. Hepatology, 42(5), 1127-1136.
Donato, F., Boffetta, P., & Puoti, M. (1998). A meta‐ analysis of epidemiological studies on the combined effect of hepatitis B and C virus
infections in causing hepatocellular carcinoma. International journal of cancer, 75(3), 347-354.
El-Serag, H. B. (2004). Hepatocellular carcinoma: recent trends in the United States. Gastroenterology, 127(5), S27-S34.
Farazi, P. A., Glickman, J., Jiang, S., Yu, A., Rudolph, K. L., & DePinho, R. A. (2003). Differential impact of telomere dysfunction on initiation
and progression of hepatocellular carcinoma. Cancer research, 63(16), 5021-5027.
Feld, J. J., Modi, A. A., El–Diwany, R., Rotman, Y., Thomas, E., Ahlenstiel, G., ... & Ghany, M. G. (2011). S-adenosyl methionine improves
early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders. Gastroenterology, 140(3), 830-839.
Fiore, G., Fera, G., Napoli, N., Vella, F., & Schiraldi, O. (1996). Liver steatosis and chronic hepatitis C: a spurious association?. European
journal of gastroenterology & hepatology, 8(2), 125-129.
Freedman, N. D., Everhart, J. E., Lindsay, K. L., Ghany, M. G., Curto, T. M., Shiffman, M. L., ... & Hoefs, J. C. (2009). Coffee intake is
associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology, 50(5), 1360-1369.
Gallus, S., Colombo, P., Scarpino, V., Zuccaro, P., Apolone, G., & La Vecchia, C. (2002). Smoking in Italy, 2002. Tumori Journal, 88(6), 453-
456.
IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151
106
Copyright © 2019 IEEE-SEM Publications
He, X. C., Yin, T., Grindley, J. C., Tian, Q., Sato, T., Tao, W. A., ... & Wiedemann, L. M. (2007). PTEN-deficient intestinal stem cells initiate
intestinal polyposis. Nature genetics, 39(2), 189.
Hu, T. H., Huang, C. C., Lin, P. R., Chang, H. W., Ger, L. P., Lin, Y. W., ... & Tai, M. H. (2003). Expression and prognostic role of tumor
suppressor gene PTEN/MMAC1/TEP1 in hepatocellular carcinoma. Cancer: Interdisciplinary International Journal of the American Cancer
Society, 97(8), 1929-1940.
Hwang, S. J., Bellocq, N. C., & Davis, M. E. (2001). Effects of structure of β-cyclodextrin-containing polymers on gene delivery. Bioconjugate
chemistry, 12(2), 280-290.
Iakova, P., Awad, S. S., & Timchenko, N. A. (2003). Aging reduces proliferative capacities of liver by switching pathways of C/EBPα growth
arrest. Cell, 113(4), 495-506.
Ikeda, K., Saitoh, S., Suzuki, Y., Kobayashi, M., Tsubota, A., Koida, I., ... & Kumada, H. (1998). Disease progression and hepatocellular
carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients. Journal of hepatology, 28(6), 930-938.
Jee, S. H., Ohrr, H., Sull, J. W., & Samet, J. M. (2004). Cigarette smoking, alcohol drinking, hepatitis B, and risk for hepatocellular carcinoma in
Korea. Journal of the national cancer institute, 96(24), 1851-1856.
Kanwal, F., Hoang, T., Kramer, J. R., Asch, S. M., Goetz, M. B., Zeringue, A., ... & El–Serag, H. B. (2011). Increasing prevalence of HCC and
cirrhosis in patients with chronic hepatitis C virus infection. Gastroenterology, 140(4), 1182-1188.
Kawai, H., Imanaga, S., & Kobayashi, T. (2000). U.S. Patent No. 6,064,082. Washington, DC: U.S. Patent and Trademark Office.
Kurozawa, Y., Ogimoto, I., Shibata, A., Nose, T., Yoshimura, T., Suzuki, H., ... & Tamakoshi, A. (2005). Coffee and risk of death from
hepatocellular carcinoma in a large cohort study in Japan. British journal of cancer, 93(5), 607.
Lechel, A., Holstege, H., Begus, Y., Schienke, A., Kamino, K., Lehmann, U., ... & Rudolph, K. L. (2007). Telomerase deletion limits progression
of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology, 132(4), 1465-1475.
Lee, J. S., & Bowen, N. K. (2006). Parent involvement, cultural capital, and the achievement gap among elementary school children. American
educational research journal, 43(2), 193-218.
Levy, M. Z., Allsopp, R. C., Futcher, A. B., Greider, C. W., & Harley, C. B. (1992). Telomere end-replication problem and cell aging. Journal of
molecular biology, 225(4), 951-960.
Llovet, J. M., Chen, Y., Wurmbach, E., Roayaie, S., Fiel, M. I., Schwartz, M., ... & Battiston, C. (2006). A molecular signature to discriminate
dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology, 131(6), 1758-1767.
Luedde, T., Beraza, N., Kotsikoris, V., van Loo, G., Nenci, A., De Vos, R., ... & Pasparakis, M. (2007). Deletion of NEMO/IKKγ in liver
parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer cell, 11(2), 119-132.
Micsenyi, A., Tan, X., Sneddon, T., Luo, J. H., Michalopoulos, G. K., & Monga, S. P. (2004). β-Catenin is temporally regulated during normal
liver development. Gastroenterology, 126(4), 1134-1146.
Mobasheri, A., Mobasheri, R., Francis, M. J. O., Trujillo, E., Alvarez De La Rosa, D., & Martin-Vasallo, P. (1998). Ion transport in
chondrocytes: membrane transporters involved in intracellular ion homeostasis and the regulation of cell volume, free [Ca^ 2^+] and
pH. Histology and histopathology, 13(3), 893-910.
Møller, H., Mellemgaard, A., Lindvig, K., & Olsen, J. H. (1994). Obesity and cancer risk: a Danish record-linkage study. European journal of
cancer, 30(3), 344-350.
Montella, M., Polesel, J., La Vecchia, C., Maso, L. D., Crispo, A., Crovatto, M., ... & Franceschi, S. (2007). Coffee and tea consumption and risk
of hepatocellular carcinoma in Italy. International journal of cancer, 120(7), 1555-1559.
Plentz, R. R., Park, Y. N., Lechel, A., Kim, H., Nellessen, F., Langkopf, B. H. E., ... & Roncalli, M. (2007). Telomere shortening and inactivation
of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology, 45(4), 968-976.
Poynard, T., Yuen, M. F., Ratzin, V., & Lai, C. L. (2003). Viral hepatitis C. The Lancet, 362(9401), 2095-2100.
Ratziu, V., Bonyhay, L., Di Martino, V., Charlotte, F., Cavallaro, L., Sayegh‐ Tainturier, M. H., ... & Poynard, T. (2002). Survival, liver failure,
and hepatocellular carcinoma in obesity‐ related cryptogenic cirrhosis. Hepatology, 35(6), 1485-1493.
IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151
107
Copyright © 2019 IEEE-SEM Publications
Rubbia-Brandt, L., Quadri, R., Abid, K., Giostra, E., Malé, P. J., Mentha, G., ... & Negro, F. (2000). Hepatocyte steatosis is a cytopathic effect of
hepatitis C virus genotype 3. Journal of hepatology, 33(1), 106-115.
Shi, J., Shen, W., Dong, X., Feng, J., Ruan, M., & Li, Y. (2005). Stimuli‐ responsive controlled drug release from a hollow mesoporous silica
sphere/polyelectrolyte multilayer core–shell structure. Angewandte Chemie International Edition, 44(32), 5083-5087.
Shimazu, T., Inoue, I., Araki, N., Asano, Y., Sawada, M., Furuya, D., ... & Greenberg, J. H. (2005). A peroxisome proliferator-activated receptor-
γ agonist reduces infarct size in transient
Talamini, R., Polesel, J., Montella, M., Maso, L. D., Crispo, A., Tommasi, L. G., ... & Franceschi, S. (2006). Food groups and risk of
hepatocellular carcinoma: a multicenter case‐ control study in Italy. International journal of cancer, 119(12), 2916-2921.
V., Wolk, Pisani, P., Tenet, A Bergström, A.., & Adami, H. O. (2001). Overweight as an avoidable cause of cancer in Europe. International
journal of cancer, 91(3), 421-430.
Wagayama, H., Shiraki, K., Yamanaka, T., Sugimoto, K., Ito, T., Fujikawa, K., ... & Nakano, T. (2001). p21WAF1/CTP1 expression and
hepatitis virus type. Digestive diseases and sciences, 46(10), 2074-2079.
Wang, Y., & Zhang, Q. (2006). Are American children and adolescents of low socioeconomic status at increased risk of obesity? Changes in the
association between overweight and family income between 1971 and 2002. The American journal of clinical nutrition, 84(4), 707-716.
White, D. L., Thrift, A. P., Kanwal, F., Davila, J., & El-Serag, H. B. (2017). Incidence of hepatocellular carcinoma in all 50 United States, from
2000 through 2012. Gastroenterology, 152(4), 812-820.
Arena, U., Vizzutti, F., Corti, G., Ambu, S., Stasi, C., Bresci, S., &Marra, F. (2008). Acute viral hepatitis increases liver stiffness values
measured by transient elastography. Hepatology, 47(2), 380-384.
Cadranel, J. F., Rufat, P., &Degos, F. (2000). Practices of liver biopsy in France: results of a prospective nationwide survey. Hepatology, 32(3),
477-481.
Castéra, L., Vergniol, J., Foucher, J., Le Bail, B., Chanteloup, E., Haaser, M., ...& de Lédinghen, V. (2005). Prospective comparison of transient
elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology, 128(2), 343-350.
Colin, C., Lanoir, D., Touzet, S., Meyaud‐ Kraemer, L., Bailly, F., Trepo, C., & HEPATIS Group. (2001). Sensitivity and specificity of
third‐ generation hepatitis C virus antibody detection assays: an analysis of the literature. Journal of viral hepatitis, 8(2), 87-95.
Crockett, S. D., Kaltenbach, T., &Keeffe, E. B. (2006). Do we still need a liver biopsy? Are the serum fibrosis tests ready for prime time?. Clinics
in liver disease, 10(3), 513-34.
Dienstag, J. L. (2002). The role of liver biopsy in chronic hepatitis C. Hepatology, 36(S1), S152-S160.
Ghany, M. G., Strader, D. B., Thomas, D. L., &Seeff, L. B. (2009). Diagnosis, management, and treatment of hepatitis C: an
update. Hepatology, 49(4), 1335-1374.
Gonzalez, M. C., Hidalgo, C. A., &Barabasi, A. L. (2008).Understanding individual human mobility patterns. nature, 453(7196), 779.
Jou, J. H., Chen, C. C., Chung, Y. C., Hsu, M. F., Wu, C. H., Shen, S. M., ... &Shyue, J. J. (2008). Nanodot‐ Enhanced High‐ Efficiency
Pure‐ White Organic Light‐ Emitting Diodes with Mixed‐ Host Structures. Advanced Functional Materials, 18(1), 121-126.
Koff, R. S. (1981). Management of the hepatitis B surface antigen (HBsAg) carrier.In Seminars in liver disease (Vol. 1, No. 01, pp. 33-43).©
1981 by Thieme Medical Publishers, Inc.
Moriya, T., Naito, H., Ito, Y., & Nakajima, T. (2009)." Hypothesis of Seven Balances": Molecular Mechanisms behind Alcoholic Liver Diseases
and Association with PPARα. Journal of occupational health, 51(5), 391-403.
Pawlotsky, J. M., Bouvier-Alias, M., Hezode, C., Darthuy, F., Remire, J., &Dhumeaux, D. (2000). Standardization of hepatitis C virus RNA
quantification. Hepatology, 32(3), 654-659.
Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L., Jameson, J. L., & Loscalzo, J. (2015). Harrison's principles of internal medicine.
McGraw Hill Education,.
IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151
108
Copyright © 2019 IEEE-SEM Publications
Mahboobi, N., Agha‐ Hosseini, F., Mahboobi, N., Safari, S., Lavanchy, D., & Alavian, S. M. (2010). Hepatitis B virus infection in dentistry: a
forgotten topic. Journal of viral hepatitis, 17(5), 307-316.
Crofts, N., Stewart, T., Hearne, P., Ping, X. Y., Breschkin, A. M., & Locarnini, S. A. (1995). Spread of bloodborne viruses among Australian
prison entrants. Bmj, 310(6975), 285-288.
Mast, E. E., Alter, M. J., & Margolis, H. S. (1999). Strategies to prevent and control hepatitis B and C virus infections: a global
perspective. Vaccine, 17(13-14), 1730-1733.
Mangia, A., Minerva, N., Bacca, D., Cozzolongo, R., Ricci, G. L., Carretta, V., ... & Cristofaro, G. (2008). Individualized treatment duration for
hepatitis C genotype 1 patients: a randomized controlled trial. Hepatology, 47(1), 43-50.
Strader, D. B., Wright, T., Thomas, D. L., & Seeff, L. B. (2004). Diagnosis, management, and treatment of hepatitis C. Hepatology, 39(4), 1147-
1171.
Backus, L. I., Boothroyd, D. B., Phillips, B. R., & Mole, L. A. (2007). Predictors of response of US veterans
IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151
109
Copyright © 2019 IEEE-SEM Publications