Hepatology, the study of liver diseases, is a broad and constantly developing medical field today which is supposed to further expand within the near future. Hepatitis is a clinical condition defined as the inflammation of liver hepatocytes. Hepatitis is associated with many etiological agents including certain hepatotropic viruses which lead to viral hepatitis (Mauss et al., 2010). The natural and clinical history of viral hepatitis dates back to early 1880s when around fifteen percent of 1,289 shipyard workers in Bremen Germany suffered from jaundice just weeks after they were vaccinated against smallpox infection with a vaccine prepared from human lymph, interestingly, unvaccinated new employees (about 500 persons) did not develop jaundice symptoms (Krugman, 1976; Colin et al., 2006; Mahoney, 1999).
Throughout the time scientists researched the viral hepatitis its etiological agents, pathogenesis and management. Here, Dr. Erwin Kuntz and his colleague Dr. Hans-Dieter Kuntz classified some multiple viruses that cause acute viral hepatitis into three different groups.
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Primary hepatotropic viruses: include the commonly known hepatitis viruses such as Hepatitis A virus (HAV), Hepatitis B virus (HBV), Hepatitis C virus (HCV) and Hepatitis Non-ABC viruses. These viruses are known to lead to a completely independent form of viral hepatitis.
Secondary hepatotropic viruses: include some Herpes viruses and enteroviruses and they mostly lead to systemic infection (with various organs being affected) as well as simultaneous and often predominant concomitant viral hepatitis.
Tropical virus infections: include some viruses that may lead to viral hepatitis and may as well at times trigger inflammatory concomitant reactions of the liver (Kuntz and Kuntz, 2006).
Detailed classification of all these hepatotropic viruses and their clinical importance, properties and symptoms, and their associated infections is shown on Table 1.
Table 1: Taxonomy of hepatotropic viruses with their importance, clinical properties, and symptoms. Adopted and modified from 'Taxonomy and Classification of Viruses' Buchen-Osmond 2003.
Signs & Symptoms
Hepatitis B virus (HBV)
Acute hepatitis which may progress to chronic hepatitis, liver cirrhosis, and primary hepatocellular carcinoma
Acute hepatitis B without Deltavirus with hepatic coma. Acute hepatitis B Without Deltavirus without hepatic coma. Chronic hepatitis B without Deltavirus
Picornaviridae, Hepatovirus Hepatitis A virus (HAV)
Hepatitis A with hepatic coma, Hepatitis A without hepatic coma
Hepatitis E virus (HEV)
Flaviviridae, Hepacivirus Hepatitis C virus (HCV)
Acute hepatitis C
Chronic viral hepatitis C
Hepatitis G virus (HGV)
Acute and chronic hepatitis
Other acute viral hepatitis
Hepatitis delta virus (HDV)
Acute and chronic hepatitis
Acute hepatitis B with Deltavirus
(coinfection)/Acute Deltavirus (super) infection of Hepatitis B carrier
Chronic viral hepatitis B with Deltavirus
Human herpesvirus 5 (HHV-5)
Cytomegalovirus mononucleosis, infectious mononucleosis
Pneumonitis, Hepatitis, Pancreatitis,
Other cytomegalovirus diseases. Disease, unspecified. Gammaherpesvirus mononucleosis. Mononucleosis
Yellow fever virus (YFV)
Sylvatic yellow fever. Urban yellow fever. Yellow fever, unspecified
HEPATITIS A VIRUS (HAV)
In early 1960s, health authorities in several different areas around the world encountered acute illness with almost same characteristics of jaundice as that caused by the serum hepatitis, one of those outbreaks was the one reported from Fort Yukon, Alaska in 1960-1961. Scientists associated this illness with poor sanitation and untreated drinking water (Maynard, 1963). Subsequently scientists recognized that there were two different forms of hepatitis infections and identified the Hepatitis A Virus (HAV) particle after years of earlier research work which had defined a lot of the clinical symptoms of the hepatitis A infection, explained the fecal-oral nature of HAV transmission, and distinguished the infection from "homologous serum jaundice," also known as hepatitis B infection (Martin and Lemon, 2006).
The causative agent of acute viral hepatitis known as infectious hepatitis was first described by Feinstone et al. in 1973 when they, with the help of immunoelectron microscopy (Kuntz and Kuntz, 2006), observed virus-like particles in feces of experimental patients infected with hepatitis A virus-contaminated material (Schmid, 2001; Kuntz and Kuntz, 2006). It was given the name proposed earlier in 1940s by Dr. MacCallam "viral hepatitis, type A," (Zuckerman, 1970).
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Hepatitis A virus particle is a nonenveloped, spherical and positive stranded RNA virus. HAV is classified within the hepatovirus genus of the Picornaviridae family. As a member of this family its genomic RNA is packaged within an icosahedral capsid which is composed of 60 copies of each of the three major structural proteins, VP1, VP2, and VP3. These proteins are also known as 1D, 1B, and 1C respectively (Martin and Lemon, 2006; WHO/CDS/CSR/EDC/2000.7, 2007). The genomic RNA of the HAV is approximately 7,500 nucleotides in length and contains one large open-reading frame (ORF) (Martin and Lemon, 2006). HAV has been classified into seven genotypes four of which infect human hepatocytes (genotypes I and III are the most common), so far, only one serotype has been reported, however, infection with any of its genotypes mostly confers a lifelong immunity against all strains of hepatitis A virus (WHO/IVB/10.01, 2009).
HAV is transmitted through the fecal-oral route either by direct contact with an infectious person or by intake of contaminated food or water, therefore, it occurs worldwide but it is highly prevalent in the developing world and the Greenland were there are socio-economically poor societies with poor sanitation measures; however, the overall global incidence of HAV infection has decreased gradually because of the improved sanitary and living conditions (Martin and Lemon, 2006; Hall, 2007; WHO/IVB/10.01, 2009). In Pakistan, Aziz (2007) reported that children above 14 years were 100% positive for anti-HAV at 14 years of age and above in Karachi (WHO/IVB/10.01, 2009), and Khan et al. (2010) reported 2.7% frequency distribution of HAV in Hazara division of NWFP province.
The most hepatitis A patients recover from the illness and the case fatality of HAV infection rate is low, the estimated mortality rate is highest in adults (2.1%) and lowest in children who are less than 15 years old (0.1%) while it is (0.3%) for adults aged 15 to 39 years (WHO/IVB/10.01, 2009). Chronic hepatitis is not associated with the HAV infection. Fore protection against this infection there are inactivated Hepatitis A viral vaccines which are highly immunogenic and protect against both infection and disease by HAV. Due to the implementation of the universal immunization program against HAV in the developed world such USA and most of the European countries there is tremendous decrease of this infection by more than 95% in children younger than 14 years of age (Martin and Lemon, 2006). It is highly recommendable to confront this infection by universal immunization against the epidemic HAV and also standardizing the sanitation and socio-economical aspects of these populations (WHO/IVB/10.01, 2009).
HEPATITIS C VIRUS (HCV)
After 1970s when hepatitis A and hepatitis B viruses were recognized, specific diagnostics have been developed for both of these agents; however, scientists recognized there was another hepatitis associated agent encountered in hepatitis patients who are negative for both HAV and HBV, at the same time the agent was blood-borne as well as transfusion-transmissible (Mahoney, 1999). In 1989 Choo et al. cloned the RNA genome of the Hepatitis C Virus (HCV) (Choo et al., 1989; Okamoto et al., 1991). Hepatitis C virus is 40-50 nm in diameter, enveloped, 9.6 kb positive-stranded RNA virus classified as a Hepacivirus of Flaviviradae family (Szabo et al., 2003; Gillcgrist, 1999; Hall, 2007). So far, six genotypes and more than 80 subtypes of HCV have been identified around the world. HCV is the most common blood-borne infection in the United States and genotype 1 is related with approximately more than 70% of all HCV infections in the US (Gillcrist, 1999; Hall, 2007). HCV transmission is classified into direct blood or fluid exposure, sexual activity, prenatal transmission, occupational exposure and potential risk factors (Zein, 2003).
Researchers have shown that HCV is not directly cytopathic virus; instead it is the viral expressed proteins which stimulate the host immune system to cause the death of the infected hepatocytes (Szabo et al., 2003). Detection of HCV RNA in the blood of a patient after initial exposure to the virus is considered as an acute hepatitis C infection. Although acute HCV infection may be severe, it is rarely associated with fulminant liver failure. Long time Chronic HCV patients develop certain complications including liver cirrhosis, end-stage liver disease, and Hepatocellular Carcinoma (HCC), however, development of these conditions varies from patient to patient (Zain, 2003). Recent studies estimate that about 75% of all HCC cases are due to chronic infections with either hepatitis B virus or hepatitis C virus (Bartosch, 2010).
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Hepatitis C virus (HCV) is a well studied hepatotropic virus; however, it has been associated with many extrahepatic manifestations as well, HCV-related cryoglobulinemia being the most prominent one as it has been diagnosed with as much as 50% of HCV patient (Szabo et al., 2003; Zein, 2003). Hepatitis C virus infects nearly 170 million people worldwide which are equivalent to about 3% of the global population (Zein, 2003; Hall, 2007). One of the latest HCV review studies in Pakistan indicates high prevalence of this infection in the region: Blood donors 3.0 %, Pregnant females 7.3%, healthy children 0.4 to 4.1% and in the general population 4.7% (Umar et al., 2010). Another study carried out in Khyber Pakhtoonkhawa (KPK) province of Pakistan reported genotype 3a as the most prevalent genotype of hepatitis C virus in Pakistan with percentage of 80.26% in that study (Ali et al., 2010).
Hepatitis C virus infection treatment is associated with many and complicated side effects that may result in discontinuity of the treatment, therefore, patients should be thoroughly educated about these possible side effects and self-management techniques to help them get through their therapy before starting it (Hall, 2007). Although there is some progress in developing certain candidate vaccines against this deadly virus, there is no vaccine for this virus yet (WHO EB126/15 126th Session 12 November 2009 Provisional agenda item 4.12). It has been very complicated to develop one because of the diversity and ability of the virus to mutate. Unlike hepatitis A and hepatitis B immunoglobulins, hepatitis C immunoglobulins do not provide effective postexposure prophylaxis; therefore, its use is not recommended (Gillcrist, 1999).
HEPATITIS D VIRUS (HDV)
In 1977, Italian physician Mario Rizzetto and colleagues isolated a novel antigen in the nucleus of hepatocytes derived from viral hepatitis patients infected with HBV in Italy. The antigen developed specific antibodies against itself when infected with hepatocytes and it was named as delta virus or hepatitis D virus (HDV) (Wedemeyer and Manns, 2010; Huang and Lo, 2010; Zuberi, 2006; Ramia, 2006; WHO/CDS/CSR/NCS/2001.1; Gillcrist, 1999). Delta antigens were associated with viral hepatitis and were found only in patients with a characteristically severe course of HBV infection. Its infection was revealed to occur only in patients who are infected with hepatitis B virus. Hepatitis D was also recognized as a defective virus that uses hepatitis B virus S-antigens (HBsAg) for its transmission and thus its infection can only occur as either co-infection with acute HBV infection or superinfection with chronic HBV infection (Wedemeyer and Manns, 2010).
Hepatitis D virus particle is approximately 36 nm and has a highly basepaired 1.7 kb long negative-sense circular RNA (the smallest genome of any animal virus) as its genome (Wedemeyer and Manns, 2010; Huang and Lo, 2010; Zuberi, 2006; Gillcrist, 1999; Hall, 2007). Recently, the Delta virus has been shown to have eight genotypes which all are spread percutaneously, by injection of drugs as well as unprotected sexual intercourse; however, percutaneous exposures are the most efficient mode of transmission for HDV (Wedemeyer and Manns, 2010). Genotype 1 is the most common genotype which is distributed throughout the world, especially in North America, Europe, the Middle East, and North Africa (Wedemeyer and Manns, 2010; Huang and Lo, 2010; Zuberi, 2006).
Hepatitis D virus is found worldwide and distribution is parallel with that of hepatitis B virus but the prevalence of HDV is different to that of HBV (Abbas et al., 2010; WHO/CDS/CSR/NCS/2001.1). The Delta virus is endemic in the Mediterranean regions, the Middle East, Asia, West & Central Africa, and Northern parts of South America (Wedemeyer and Manns, 2010; Hall, 2007; WHO/CDS/CSR/NCS/2001.1).
More than 350 million people are thought to have chronic HBV infection worldwide; about 10-20 million of these individuals are thought to be either coinfected or superinfected with HDV (Abbas et al., 2010; Wedemeyer and Manns, 2010). Recent HDV prevalence studies in Pakistan have shown a quite higher prevalence on the infection among HBsAg-positive patients. 58.6% in Karachi and Jacobabad, however, earlier studies noted 16.6% prevalence of the same infection. The increase is thought to be due to reuse of unsafe needle injections for drugs, sexual transmission surgical and dental razors barber razors, and injecting drug abuse (Abbas et al., 2010). Hepatitis D viral infection is the only viral hepatitis infection with no established treatment, although, some therapeutic strategies can be employed such as pegylated interferon alfa (PeG-iFn-Î±) for at least 1 year (Wedemeyer and Manns, 2010).
HEPATITIS E VIRUS (HEV)
Hepatitis E virus (HEV) was first identified in Asia (Pelosi and Clarke, 2008). HEV shares some basic epidemiological and clinical properties with HAV, therefore, it was misunderstood as HAV for many years but. in late 1970s HEV was describes as enterically-transmitted/epidemic non-A, non-B hepatitis (www.who.int water_sanitation_health). The suspected virus in pooled faecal extracts from human epidemic of non-A non-B hepatitis was experimentally infected to a volunteering person and in 1983 researchers isolated small virus like particles by using immune electron microscopy from the same patient thus confirming the HEV (Pelosi and Clarke, 2008). Despite the many features HEV shares with HAV, viral hepatitis E occurs more often in young adults. Hepatitis A rarely causes severe complications, while hepatitis E virus is associated with more prominent cholestasis with the possibility of the infection becoming acute fulminant hepatitis, particularly in pregnant women, whose case fatality rates are as high as 20-40% (www.who.int water_sanitation_health).
HEV is a positive sense single stranded RNA virus (Pelosi and Clarke, 2008; Hall, 2007; Gillcrist, 1999). It is 27-30nm in diameter, icosahedral, non-enveloped virus (Pelosi and Clarke, 2008; Gillcrist, 1999). HEV was initially classified as a member of Caliciviridae family, however, in 2004, it was re-classified in Hepeviridae family and it is the single member of the genus Hepevirus (Pelosi and Clarke, 2008). Based on differences in its genome, HEV has been assigned to have four major genotypes with each genotype having several subtypes (Pelosi and Clarke, 2008; Hall, 2007). HEV is a waterborne infection transmitted through the faecal-oral route; therefore, it is prevalent in the developing countries because of the poor sanitation measures (Pelosi and Clarke, 2008; WHO/CDS/CSR/EDC/2001.12). HEV infections and outbreaks have already been recorded in many countries in Asia, America and Africa (www.who.int water_sanitation_health).
In 1993/1994, 10.4% rated HEV outbreak in Islamabad was reports to have killed four adults who all were pregnant women (Alavian et al., 2009). One study conducted in Karachi to study HEV prevalence among pregnant women reported 57% HEV infection. Recently carried out and large overview study investigated the data from 5193 cases for general viral hepatitis with HEV accounting no less than 20.2% of the positive viral hepatitis cases (Ahmed et al., 2010).
Despite the many attempts to develop protective vaccine against HEV there is no ready vaccine today though some are reported to be in clinical trials. HEV treatment is also primarily supportive. The best prevention measures are avoiding ingestion of contaminated food and water, sewage as well as and uncooked foods (Pelosi and Clarke, 2008; Hall, 2007).
HEPATITIS F VIRUS (HFV)
Hepatitis F virus has been reported but it has not been classified. Many questions about the existence of this virus remain un-answered. It has been reported to cause sporadic cases associated with water-borne transmission of hepatitis virus other than HAV and HEV (www.who.int water_sanitation_health). HFV has been reported as double-stranded DNA, non-enveloped icosahedral virus, with 27-37nm diameter (Deka et al., 1994).
HEPATITIS G VIRUS (HGV)
Hepatitis G virus (HGV) also known as GB-Virus was discovered by two research groups working independently during their study of non-A, non-B, non-E viral hepatitis infections and their suspected etiological agents (Reshetnyak et al., 2008; Gillcrist, 1999). The discovery followed a report from the illness of American surgeon G. Barker (GB), who was diagnosed with acute hepatitis with moderate enzymatic activity and three-week icteric period in 1966. Blood sample of the surgeon was used to infect laboratory animals and all subject animals developed hepatitis symptoms (Reshetnyak et al., 2008; Carman, 1998). 25 years later with the development of the new viral qualitative techniques the GB researchers isolated two viral genomes from animal sera of GB infected animals. GBV-A and GBV-B were closely-related viruses and were classified in the Flaviviridae family. By using primers designed to the well conserved NS3-region of GBV-A, GBV-B and HCV, another virus was identified as GBV-C. The new GBV-C was genetically related to the old HGV, hence it was considered as independent hepatotropic agent (Reshetnyak et al., 2008).
Epstein et al. (2010) isolated another unique GB virus genome sequence from Old World frugivorous bats (P. giganteus) in Bangladesh. They have identified and isolated two full-length sequences that share approximately 50% amino acid sequence identity with GBV-A and GBVC/ HGV, therefore, the new virus was named GBV-D (Stapleton et al., 2010). Just a few months before (17-11-2010), Stapleton et al. (2010) submitted a paper to suggest classification of GBV-A, GBV-A-like agents, GBV-C/HGV and GBV-D in a new genus with the name (Pegivirus) within the family Flaviviridae. The suggested classification is based on their genome structure, phylogenetic relationships, lack of pathogenicity and ability to persist in vivo. HGV has a single chain of positive sense single stranded RNA genome which is approximately 9.4 kb in length and resembles with that of HCV in its organization (Reshetnyak et al., 2008; Praharaj et al., 2005). Hepatitis G virus is clearly a blood-borne virus as it is transmitted by blood and blood products as well as by sexual route (Praharaj et al., 2005; Gillcrist, 1999). Hepatitis G has a worldwide distribution (Reshetnyak et al., 2008; Hall, 2007) with non-uniformity in all ethnic groups including Caucasians, Asians and Africans. The detection average of GBV-C is 1.7% in the world population (Reshetnyak et al., 2008). Since GB viruses are blood-borne their only control and management is to avoid reuse of drug needles and to maintain high protective measure in hospital and dental practices (Reshetnyak et al., 2008).
INTRODUCTION TO HEPATITIS B VIRUS (HBV) AND ITS ASSOCIATED VIRAL HEPATITIS
Hepatitis B Virus (HBV) is genuinely the prototype member of Hepadnaviridae family which replicate within the liver hepatocytes (Ganem and Prince 2004; Schaefer, 2007). HBV infection is not a simple infection that leads to single liver disease. It is associated with a wide spectrum of liver disease such as acute hepatitis with or without fulminant hepatic failure, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) (Liang, 2009; Elgouhari et al., 2008). Hepatitis B virus infection is clinically one of the most important infectious diseases associated with significant morbidity and mortality rates worldwide (Mauss et al., 2010; Colin et al., 2006). Hepatitis B virus infection is the 10th leading cause of death worldwide and HBV associated hepatocellular carcinoma (HCC) alone claims 300,000 to 500,000 lives each year, and so is the 5th most frequent cancer worldwide (Lavanchy, 2004).
This virus can be transmitted by multiple routes including perinatal/mother-to-infant, percutaneous, permucosal exposure to infectious blood or body fluid, by unprotected sexual contact with infected persons and occupational/health-care-related (Edey et al., 2010; Dienstag, 2008; Colin et al., 2006; Mahoney, 1999). Chronic HBV patients are believed to be the major reservoir for transmission; however, any individual who tests positive for HBsAg is also potentially infectious (Colin et al., 2006). The epidemiology, prevalence and frequency of transmission of hepatitis B infection in the world varies significantly in different geographic areas of the world, and therefore, in different population groups (Mauss et al., 2010; Lavanchy, 2004; Mahoney, 1999). Earlier in mid 1990s Pakistan has been regarded to happen in regions with high endemicity of hepatitis B infection (Tanveer et al., 2008), but currently as per documentations of the World Health Organization (WHO) Pakistan is included in the intermediate endemicity region of Hepatitis B infection with HBV prevalence of 3% in its population (Alam et al., 2007-a).
The hepatitis B virus genome is a 3.2 kbp partially double-stranded DNA that encodes four well established and overlapping open reading frames termed as surface/S-gene, core/C-gene, polymerase/P-gene and X-gene. As much as ten HBV genotypes (A-J) have been reported based on more than 8% divergence of entire HBV genome, however, eight genotypes (A-H) remain well studied while some questions still remain unanswered over the two lately identified genotypes (i.e. I and J) (Cao, 2009).
The eight (A-H) HBV genotypes which are well characterized show very distinct geographical distribution and also influence the clinical outcome, prognosis, and response to antiviral treatment (Cao, 2009; Chen, 2004). Some of these genotypes have been possibly associated with extra severity of the disease such as possible development of hepatocellular carcinoma (Pan and Zhang, 2005). Keeping all these importance in mind, number of different techniques used for the detection of these genotypes have been developed which can be basically classified into genotyping methods based on nucleotide sequences and genotyping methods based on serological detection of HBV genotypes (Miyakawa and Mizokami, 2003).
These hepatitis B virus genotype detection techniques have their unique characteristics, however, the number of comparative studies which actually compared many of these assays have been limited (Wang et al., 2007). Moreover, according to a study by Alam et al., (2007a), the prevalence rate of HBV in Pakistan was higher in its low socioeconomical populations compared with the rich populations. This reason emphasizes the need of cheap and affordable hepatitis B virus genotype detection methods in the developing world including Pakistan. In order to further extend the technical efficiency and importance of these genotyping techniques and to assess their exact credibility some comparative studies have been carried out from time to time.