Epidemiology and Etiology of Hepatocellular …...Hepatocellular carcinoma (HCC) accounts for...

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

IEEE-SEM, Volume 10, Issue 6, June-2019 ISSN 2320-9151

91

Copyright © 2019 IEEE-SEM Publications

mailto:[email protected]



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.


98


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


99


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)


100


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


101


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.

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journal of gastroenterology & hepatology, 8(2), 125-129.

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456.


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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.

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Epidemiology and Etiology of Hepatocellular …...Hepatocellular carcinoma (HCC) accounts for...

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