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Anna Giulia Cattaneo, M.D.
HCV infection is one between different viral aggression possibly
affecting the human liver, and mainly hepatocytes, with a
parenteral diffusion pattern. Tab. 1 is a rapid summary of
different types of viral hepatitis affecting humans, showing
main features of their agents, preminent modalities for interpersonal
transmission and usual evolution patterns. Among them HCV
infection represents an acute pathology usually limited to
the young, but its slowly evolving sequences are responsible
for an increased risk in the elderly. The severity of evolution
- chirrosis and hepatic carcinoma - are even enhanced by coexisting
and usually live long pathogenic agents, like alchol and drug
abuse, multiple exposures to the agent and coinfection with
other hepatotropic viruses.
Table 1 : Hepatotropic viral agents affecting humans.
The pathogenicity of HGV and of TT virus, similar to circovirus
and newly proposed as hepatotropic, is under debat.
Because of its high frequence, association of unresolved HCV
infection with cirrhosis and hepatocellular carcinoma and
the lack of efficaciuos vaccine, HCV infection may generate
very expensive burdens for Europe, USA and worldwide, if preventive
measures of only limited efficacy should be adopted. Despite
of its importance, studies on prevalence and incidence in
population appears to be lacking predictivity concerning the
future of this disease and its late consequences.
Table 2 summarizes recent studies on prevalence of HCV infection.
Table 2 . Recent studies on the prevalence of HCV
infection.
In all studies here reported infection has been stated by
criteria generally recognized. Anti HCV positivity has been
stated by a screening immunoenzymatic assay, followed by confirmatory
test in positive subjects (immunoblotting, RIBA) and by PCR
to check the persistent viremia in those resulting positive
to the confirmatory test.
Associated risk factors and preventive measures.
1) In search of an effective vaccine
As other viral infections spread worldwide in last decades,
like HIV, also the HCV shows an elusive behaviour escaping
rapid preparation of a safe vaccine able to induce an efficacious
and persistent immunity in recipients. Viral antigens variability
and the lack of a reliable cell culture system frustrated
the attempt performed until now.
At the present, attention of researchers appears to be focused
on HVR1 and CD81 viral antigens. A promising attempt has been
performed by inducing HCV-like particles (HCV-LPs) in insect
culture cells. These antigens appears to be able to induce
the production in mice of IgG1 anti HCV E1/E2. If combined
with adjuvants, the anticorpal title rises up to 10 times,
and the immunitary response appears to be more complete, inducing
IgG2 secretion too: this last finding should be due to the
specific action of adjuvant on T-helper type1 cells. No attempts
have been performed in humans exposed to the infection or
multiple infection risks.
Another possibility could be the preparation af a non proteic
vaccine, with recombinant DNA.
Different vectors of HCV genes have been checked and proved
effective in immunization of HLA-A21- transgenic mice.
2) Acute infection and spreading : preventive measures.
The lack of a suitable vaccine,in addiction to therapeutic
means expensive and with limited efficacy, forces the specialist
to obtain effective means of prevention for infection, reinfection,
spread of infection and chronic evolution of the disease principally
by using igienic and behavioural measures. A serious knowledge
of risk factors and modalities of transmission of viral infection
is the most important basis for it.
Main risk factors for HCV infection are generally recognized
as the inoculation or contact (percutaneous or mucosal) with
infected blood and derivatives, other body secretions or tissues.
Even animals can be carriers of infections: dog bites can
often be an anamnestic finding in infected patients. Subjects
exposed to high risk of infection and possibly responsible
for the spread of virus in population could be ideally divided
into three areas: individuals with degraded or hazardous life
styles, patients affected by special pathologies, and the
workers in certain sanitary areas. In details, drug abuse,
expecially intravenous and without needle and syringes control,
tatooing, body piercing, scarifications ritual or not, contacts
with multiple sexual partners are the principal modalities
of infection for the first area. Previous carcerations are
associated with high prevalence of infection due to the frequency
of risk behaviour among prisoners. In population with hazardous
behaviour, anti HCV positivity frequently cohexists with other
blood borne or sexually transmitted diseases, and expecially
with HBV and HIV infections.
Among the illnesses associated with higher risk of infection,
attention should be payed to patients submitted to hemodialysis,
blood transfusions or infusions with blood derivatives, recipients
of organ transplantations and in certain cases even people
requiring dental care. However, in these cases the incidence
of infection among patients has been effectively reduced after
the adoption of safe and severe control screening protocols.
On the contrary, the high prevalence of antiHCV positivity
observed in certain cases in subjects admitted to psychiatric
clinic appears to be not related to the mental illness itself
and its consequences, but confined to subjects having a life
style at risk, like drug abusers.
Finally, HCV infection as a professional risk should be recognized
for sanitary workers professionally exposed to the risk of
contact with contaminated material: those working in hemodialysis
or in chirurgical departments, or manipulating needles, scalpels
sanitary discard material or having frequent contact with
at risk patients (like drug abusers). In these people an efficacious
strategy for early diagnosis of infection and prevention of
its chronicity should be introduced as a routine. Recommended
maesures at the present (in the absence of a vaccine) are
the postexposure control of anti HCV positivity and the level
of alanine aminotransferase (ALT), carried out in the proximity
of the insult if possibly contaminated material has been accidentally
inoculated, or 6 months later if the contact has been percutaneous
or mucosal. In the case of documented infection, it should
be cured with a standard antiviral therapy, to avoid chronic
evolution.
A particular modality of infection is the vertical transmission
from the mother to the newborne: a study carried out in Norway
reports a prevalence of 8.3% of newborne from mother with
persistent viremia (RNA-HCV positive). Another work describes
a negative association between HCV vertical infection and
the presence of the antigen HLA-DR13, and propose a protective
role of this locus by enhanced cellular immunity. Transmission
is perinatal, breast feeding does not transmit the infection.
The PCR is usually negative at the birth, but could persist
for 12 until a maximum of 18 months after: 25% of positive
show elevated ALT serum levels. Need of therapy is under debat.
All those consideration describe HCV infection and acute
disease as an illness confined or by far more frequent in
young population.
Preventive measures in these cases are to be planned as following:
- early identification and diagnosis of infection in subjects
at risk with a standard protocol (anti HCV screening test,
confirmatory RIBA in positive subjects, PCR in confirmed
anti HCV positive)
- cautious control of blood and its derivatives, viral
inactivation, screening of positive donors
- control of tissues for transplantation
- screening and prevention of accidental infections in
sanitary workers, treatment of acute infection to reduce
persistent viremia
- health education of general population, population at
risk, sanitary workers. Diffusion of reports and protocols
concerning the modalities of infection, new preventive measures
risk evaluation etc. between physician communities, politic
bureaux, spontaneous association of healthy volunteer, education
and prevention in middle and high school.
- Severe control of igienic precautions in every care facilities
(dentistry studies, laboratories , hemodialysis and surgical
departments), correct and protected discard of all contaminated
material.
- Cautions with residents in protected houses for at risk
people as drug users, prisoners after dimissions from correttional
settings, drug addicts that escape sanitary control and
in general with all people having a hazardous behaviour.
In these cases the prevention is difficult and often frustrating:
a quite realistic aim could be the restriction of infection
spread in general population and the treatment of acute
cases requiring cure.
Treatment of acute infections could be even an efficacious
preventive measure to avoid spread of virus, if it abolishes
the viremia. HCV infection require therapy in selected and
well stated cases, on the basis of the presence of viremia
and active and persistent hepatic disease documented by ALT
raising in serum and by liver biopsy.
3) Chronic sequelae and HCV infection in adult and old
indivuals.
HCV infection has a typical long term course; this fact could
explain how an illness having its acute onset in the younger
shows higher prevalence in the elderly and has its more severe
complications in aging people. The Dionysos protocol, performed
in 1991-1993, stated a 8% prevalence in aged people, while
it was only 3.2% in general population. These results are
limited to the areas of the Northern Italy and to the period
in which the observations have been carried out: being HCV
described as an individual pathogenic factor only in 1989,
prevalence observed in 1991-1993 describes the situation existing
before preventive measures could be adopted. This fact may
explain the prevalence in general population higher than in
other reports. Another study from Poland confirmed higher
prevalence of infection signs in older people.
Even higher prevalence, however, was found in aged subjects
(60-to-90 years, divided into three decades) matched for age
suffering or not from cataract : a presumptive role of infection
on lens degeneration has been proposed. Cirrhosis, both compensated
or not, and evolution as hepatocellular carcinoma are the
preminent long term complications of an infection frequently
evolved in a paucisymptomatic manner. Antiviral combined therapy
is recommended only in RNA-HCV positive patients suffering
from compensated cirrhosis with elevated ALT and high score
for active disease in liver biopsy: at least 15-20% of these
subjects could be effectively cured, obtaining slower progeression
of hepatic damage.
No antiviral treatment is efficacious in scompensated cirrhosis
or hepatocellular carcinoma, in which palliative care and
eventually transplantation (for carcinoma) could be required.
Attention should be payed to the possibility of reinfection
of the transplanted liver.
In the elderly, the American NHI does not define the need
for antiviral treatment: in fact, the complete therapy may
be too expensive in comparison with life expectancy and quality,
in the presence of extra-hepatic pathologies generally affecting
older people. Igienic improvement and mainly reduction of
alcohol consumption in aged indivisuals are preminent measures
to ameliorate welfare and to reduce risk of cirrhosis evolution
and of other major complications of the infections in this
class of age.
Conditions associated to severe sequelae are multiple reinfection,
as those occuring in subjects with at risk behaviour or in
multiple transfusion recipient in the past, and exposure to
dietary, infectious or pharmacological liver insults. Among
them, the co- and overinfection with HBV and HIV, or other
hepatotropic blood borne viral infections, therapeutic or
recreative use of drugs, malnutrition and alcohol abuse are
the most frequently observed.
The epidemiology of HCV infections differs in different groups
of age, and in patients suffering from cirrhosis or hepatocellular
carcinoma.
HCV-RNA (+), present in 2.3% of all patients anti HCV (+)
in the Italian study, was higher in female (M/F = 0.7) and
in the older. The incidence of hepatocellular carcinoma was
3% per year only in HCV-RNA positive subjects with cirrhosis
and history of heavy drinking. The genotype 1b (prevalence
in viremic subjects: 42%) is associated to cirrhotic or carcinomatous
evolution. Genotype association with hepatocellular carcinoma
development is complicated by the relevance recently recognized
to two point-mutations in the viral genoma of subtype 1b genotype.
The mutant sequences have been found in cancerous and adjacent
normal tissues: they are coding the viral core protein, a
postulated starter of hepatic carcinogenesis thougether with
F protein. Both proteins share mutant N-terminal sequence
of 11 Aa residues only present in patients with hepatocellular
carcinoma.
A retrospective, autoptic study showed the following pattern
of HCV infection prevalence in a sample of Italian population
suffering from hepatic cirrhosis:
- 1969-1979 : 35-38%
- 1984 : 65%
- 1989 : 77% (peak)
- 1994 : 50%
Genotype 1 is by far the most frequently present in these
material (89%). In addition, in patients with evolution of
viral infection as cirrhosis or carcinoma higher levels of
a leukocytic marker of DNA oxidative damage, namely 8 OH-desoxyguanidine,
are present, suggesting a role in evolution of hepatocellular
damage
Anti HCV positive subjects, and expecially those with viremia
and chronic liver disease, shows higher frequence of non-organ
specific autoantibody (NOSAs).
Recently, in an Italian sample of population the following
distribution of viral genotypes have been observed:
- 1a (22% frequence) is most frequently observed in people
aged 0-15 years; it is associated to drug abuse and its
frequence declines after age 45
- 1b (35.5%) is more frequent in people aged 16-30 years,
in community acquired infections and in patients with late
sequelae as cirrhosis and carcinoma (89% positivity in autoptic
liver affected by cirrhosis and HCV infection). It is persistently
present in aged 45 or more.
- 3a (21.4%) is most frequently observed in people aged
31-45 years; it is associated to drug abuse and its frequence
declines after age 45.
- 2 (21%) is the most prevalent genotype present after age
45, present with genotype 1b in up to 90% of positive subjects.
It is associated to community acquired infections.
From data here exposed, it should be possible that some
variation in the epidemiology of HCV infection in the older
will be observed in the near future, when ageing of survivals
from drug abuse will be responsible of a major portion of
older people living in communities for the elderly.
It is possible to postulate in the future a decreased frequence
of community acquired infections, due to amelioration of
igiene, health education and screening of potentially contagious
subjects. In that case the prevalence of the dangerous genotype
1b and of associated severe illnesses may be reduced, and
HCV infection shifted to a more simple disease.
The hope for a suitable vaccine and efficacious, possibly
not expensive therapy are even more promising goals.
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Dipartimento di Biologia Strutturale e Funzionale, Università
dell'Insubria, Varese.
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