History
Hepatitis C virus (HCV) is a major cause of progressive liver disease with
approximately 130-170 million people infected worldwide. HCV induces chronic
infection in up to 80% of infected individuals. The main complications of HCV
infection are severe liver fibrosis and cirrhosis, and 30-50% of individuals with
cirrhosis go on to develop hepatocellular carcinoma (Tong 1995, Poynard 1997).
Until 1975, only two hepatitis viruses had been identified, the “infectious hepatitis
virus” (hepatitis A virus, HAV) and the “serum hepatitis virus” (hepatitis B virus,
HBV). However, other viruses were excluded from being the cause of
approximately 65% of post-transfusion hepatitis. Therefore, these hepatitis cases
were termed “non-A, non-B hepatitis” (NANBH) (Feinstone 1975). Inoculation of
chimpanzees (Pan troglodytes) with blood products derived from humans with
NANB hepatitis led to persistent increases of serum alanine aminotransferase (ALT)
indicating that an infectious agent was the cause of the disease (Alter 1978,
Hollinger 1978). Subsequently, it was demonstrated that the NANBH agent could
be inactivated by chloroform (Feinstone 1983). Moreover, it was reported that the
infectious agent was able to pass through 80 nm membrane filters (Bradley 1985).
Taken together these findings suggested that the NANBH causing agent would be a
small virus with a lipid envelope. However, the lack of a suitable cell culture system
for cultivation of the NANBH agent and the limited availability of chimpanzees
prevented further characterization of the causative agent of NANBH for several
years. In 1989, using a newly developed cloning strategy for nucleic acids derived
from plasma of NANBH infected chimpanzees the genome of the major causative
agent for NANBH was characterized (Choo 1989). cDNA clone 5-1-1 encoded
immunological epitopes that interacted with sera from individuals with NANBH
(Choo 1989, Kuo 1989). The corresponding infectious virus causing the majority of
NANBH was subsequently termed hepatitis C virus (HCV).
HBV Virology
Introduction
The human hepatitis B virus (HBV) is a small enveloped DNA virus causing acute
and chronic hepatitis. Although a safe and effective vaccine has been available for
the last two decades, HBV infection still represents a major global health burden,
with about 350 million people chronically infected worldwide and more than 1
million deaths per year due to HBV-associated liver pathologies (Block 2007).
Many epidemiological and molecular studies have shown that chronic HBV
infection represents the main risk factor for hepatocellular carcinoma development
(Shepard 2006, Lok 2004, Pollicino 2011). The rate for chronicity is approximately
5% in adult infections, but it reaches 90% in neonatal infections. HBV transmission
occurs vertically and horizontally via exchange of body fluids. In serum, up to 1012
HBV genome equivalents per ml serum can be found. Although HBV does not
induce direct cytopathic effects under normal infection conditions (Wieland 2004,
Thimme 2003), liver damage (fibrosis, cirrhosis, and eventually hepatocellular
carcinoma) is believed to be induced by the ongoing immune reaction and a
consistent inflammation of the liver (McMahon 2009, Chisari 2007).
HBV is the prototype member of the Hepadnaviridae family, which are the
smallest DNA-containing, enveloped animal viruses known. Characteristic of HBV
is its high tissue- and species-specificity, as well as a unique genomic organization
with asymmetric mechanism of replication (Nassal 2008). Since all hepadnaviruses
use a reverse transcriptase to replicate their genome, they are considered distantly
related to retroviruses. Despite decades of research and significant progresses in
understanding of the molecular virology of HBV, important steps of the infection,
such as the mechanism and cellular receptor(s) mediating viral entry, have not yet
been clarified (Glebe 2007). Only recently, innovative infection models and
molecular techniques have opened new possibilities to investigate specific steps of
the lifecycle, as well as the organization and the activity of the covalently closed
circular DNA (cccDNA), the viral minichromosome serving as the template of HBV
transcription in the nucleus of the infected hepatocytes, which enables maintenance
of chronic HBV infection (Levrero 2009).
Hepatitis E: an underestimated problem?
Introduction
Hepatitis E is an inflammatory liver disease caused by the hepatitis E virus (HEV),
which is endemic in many tropical countries. Hepatitis E has been considered to be
a travel-associated, acute, self-limiting liver disease that only causes fulminant
hepatic failure in specific, high-risk groups. It has recently been estimated that HEV
infection causes approximately 70,000 deaths each year worldwide (Rein 2011). In
recent years sporadic cases of HEV infections have emerged also in industrialized
countries, mostly caused by HEV genotype 3, for which zoonotic transmission has
been described (Pischke 2010b).
In immunocompetent individuals infection with HEV usually leads to a clinically
silent seroconversion or to an acute self-limited inflammation of the liver. In
pregnant women and patients with pre-existing chronic liver diseases cases of
fulminant liver failure by HEV infection are reported (Pischke 2010b).
Moreover, cases of chronic HEV infection associated with progressive liver
disease have been described in several cohorts of immunocompromised individuals.
In this context, diagnosis of HEV infection should rely on detection of HEV RNA,
as testing for HEV-specific antibodies may lack sensitivity (Pischke 2010c).
Therapeutic options for chronic hepatitis E include reduction of
immunosuppressive medication (Kamar 2011a), treatment with α-interferon
(Haagsma 2010, Kamar 2010a) or therapy with ribavirin (Kamar 2010b, Mallet
2010).
Recently, results of a large Phase III study were presented investigating a novel
recombinant HEV vaccine in China. The vaccine had an efficacy to prevent acute
symptomatic hepatitis E of >90% (Zhu 2010). It is unknown yet if and when this
vaccine might become available for other countries.
Hepatitis C
Epidemiology
Hepatitis C is a disease with a significant global impact. According to the World
Health Organization there are 130-170 million people infected with the hepatitis C
virus (HCV), corresponding to 2-2.5% of the world’s total population. There are
considerable regional differences. In some countries, e.g., Egypt, the prevalence is
as high as 22% (WHO 2011). In Africa and the western Pacific the prevalence is
significantly higher than in North America and Europe (RKI 2004).
It is estimated that there are 2-5 million HCV-positive persons in Europe. The
prevalence of HCV antibodies in otherwise healthy blood donors is approximately
1.6% in the United States, 1.15% in Italy, 0.4% in Germany, and 0.23% in
Scandinavia (RKI 2004, Hatzakis 2011). The number of patients HCV RNApositive
is estimated to be around 80 to 90% of all HCV antibody-positive persons.
Certain groups are preferentially affected: The highest risk factor in most cases is
injection drug use. But patients undergoing hemodialysis and persons who received
blood transfusions before 1991 are at risk also. In Europe and the United States
chronic hepatitis C is the most common chronic liver disease and the majority of
liver transplants performed are for chronic HCV.
It is difficult to determine the number of new HCV infections, as most acute cases
will not be noticed clinically. Fewer than 25% of acute cases of hepatitis C are
clinically apparent (Vogel 2009). In addition, the age of infection upon diagnosis is
not possible to determine in most cases. Nevertheless, it has to be assumed that the
number of new infections has considerably decreased over the past decades. For the
United States it is estimated that the number of new cases of acute HCV infection
has fallen from approximately 230,000 per year in the 1980s to about 20,000 cases
per year currently (Wasley 2008). This decrease is primarily associated with
reduced infections in injection drug users, a probable consequence of changes in
injection practices motivated by education about human immunodeficiency virus
(HIV) transmission. Transfusion-associated hepatitis C has had little impact on this
decline, as the number of cases has been reduced almost to zero. The only different
trend is an increase in acute hepatitis C infections in HIV-positive men who have
sex with men (MSM) globally over the last decade (Boesecke 2011).
Hepatitis B
Introduction
It is estimated that approximately 30% of the world’s population has had contact
with or are carriers of the hepatitis B virus (HBV). An estimated 350 million of
them are HBV carriers (Goldstein 2005). Thus, HBV infection is one of the most
important infectious diseases worldwide. Around one million persons die of HBVrelated
causes annually. There is a wide range of HBV prevalence rates in different
parts of the world. HBV prevalence varies from 0.1% up to 20%. Low prevalence
areas (0.1-2%) are Western Europe (with wide variation within Europe), United
States and Canada, Australia and New Zealand; intermediate prevalence (3-5%) are
the Mediterranean countries, Japan, Central Asia, the Middle East, and Latin and
South America; and high prevalence areas (10-20%) include southeast Asia, China,
and sub-Saharan Africa. This diversity is probably related to differences in age at
infection, which correlates with the risk of chronicity. The progression rate from
acute to chronic HBV infection decreases with age. It is approximately 90% for an
infection acquired perinatally, and is as low as 5% (or even lower) for adults
(Stevens 1975, Wasley 2008).
The incidence of new infections has decreased in most developed countries, most
likely due to the implementation of vaccination strategies (Rantala 2008). However,
exact data is difficult to generate as many cases remain undetected due to the
asymptomatic nature of many infections (RKI 2007, CDC 2010). Nevertheless, in
Germany 2524 cases of acute hepatitis B were documented in the year 2006,
corresponding to an incidence rate of 1.4 per 100,000 inhabitants. In 1997 there
were 6135 documented cases of acute hepatitis B. Likewise, the incidence of acute
hepatitis B in the United States has decreased by 78% from 1990 to 2005 (Wasley
2008). It is expected that this number will further decrease in countries with
implementation of vaccination programs. In Germany 87% of all children starting
school were fully vaccinated in 2006 with a trend toward increasing coverage
(Poethko-Muller 2007). Interestingly, recent data from a Swiss clinic indicate that
uptake in HBV vaccinations is significantly higher when vaccination is endorsed by
nurses rather than the patients’ physician (Blanco 2011). Although the incidence of acute HBV infection has decreased in most countries
due to the implementation of vaccination programs, HBV-related complications
such as cancers and deaths have been on the increase (Gomaa 2008, Hatzakis 2011).
Reasons might be the delay of vaccination effects, improved diagnosis, and better
documentation of HBV cases. Although a drop in prevalence has been observed in
many countries, estimates are difficult due to a continuously growing migration
from high or medium prevalence areas to low prevalence areas (Belongia 2008).
Hepatitis A
The virus
Hepatitis A is an inflammatory liver disease caused by infection with the hepatitis A
virus (HAV). HAV is a single-stranded 27 nm non-enveloped, icosahedral RNA
virus, which was first identified by immune electron microscopy in 1973 (Feinstone
1973). The virus belongs to the hepadnavirus genus of the Picornaviridiae.
Seven different HAV genotypes have been described, of which four are able to
infect humans (Lemon 1992).
The positive-sense single-stranded HAV RNA has a length of 7.5 kb and consists
of a a 5’ non-coding region of 740 nucleotides, a coding region of 2225 nucleotides
and a 3’ non-coding region of approximately 60 nucleotides.
Epidemiology
HAV infections occur worldwide, either sporadically or in epidemic outbreaks. An
estimated 1.4 million cases of HAV infections occur each year. HAV is usually
transmitted and spread via the fecal-oral route (Lemon 1985). Thus, infection with
HAV occurs predominantly in areas with lower socio-economic status and reduced
hygienic standards, especially in developing, tropical countries. In industrialised
countries like the US or Germany the number of reported cases has decreased
markedly in the past decades, according to official data published by the Centers for
Disease Control and Prevention (CDC, Atlanta, USA) and the Robert Koch Institute
(RKI, Berlin, Germany) (Figure 1). This decrease is mainly based on improved
sanitary conditions and anti-HAV vaccination. Vaccination programs have also
resulted in fewer HAV infections in various endemic countries including Argentina,
Brazil, Italy, China, Russia, Ukraine, Spain, Belarus, Israel and Turkey (Hendrickx
2008).
What is Cancer? What Causes Cancer?
What is Cancer? What Causes Cancer?
Retweet Cancer is a class of diseases characterized by out-of-control cell growth. There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected.
Cancer harms the body when damaged cells divide uncontrollably to form lumps or masses of tissue called tumors (except in the case of leukemia where cancer prohibits normal blood function by abnormal cell division in the blood stream). Tumors can grow and interfere with the digestive, nervous, and circulatory systems, and they can release hormones that alter body function. Tumors that stay in one spot and demonstrate limited growth are generally considered to be benign.
More dangerous, or malignant, tumors form when two things occur:
a cancerous cell manages to move throughout the body using the blood or lymph systems, destroying healthy tissue in a process called invasion
that cell manages to divide and grow, making new blood vessels to feed itself in a process called angiogenesis.
When a tumor successfully spreads to other parts of the body and grows, invading and destroying other healthy tissues, it is said to have metastasized. This process itself is called metastasis, and the result is a serious condition that is very difficult to treat.
In 2007, cancer claimed the lives of about 7.6 million people in the world. Physicians and researchers who specialize in the study, diagnosis, treatment, and prevention of cancer are called oncologists.
What causes cancer?
Cancer is ultimately the result of cells that uncontrollably grow and do not die. Normal cells in the body follow an orderly path of growth, division, and death. Programmed cell death is called apoptosis, and when this process breaks down, cancer begins to form. Unlike regular cells, cancer cells do not experience programmatic death and instead continue to grow and divide. This leads to a mass of abnormal cells that grows out of control.