The History of Hepatitis C

Hepatitis C is a form of hepatitis caused by an RNA (Ribo Nucleic
Acid) virus, and accounts for most of the hepatitis cases previously
referred to as non-A, non-B hepatitis. The Hepatitis C Virus (HCV)
was first identified in 1988 and a hepatitis C antibody test
(anti-HCV) to identify individuals exposed to HCV became
commercially available in 1990. In 1995 the hepatitis C virus was
seen for the first time by using an electron microscope.

The hepatitis C virus has a high mutation rate. These ongoing
changes in the virus make it difficult for the body's own immune
system to fight it off, as by the time the immune system figures out
the virus, it has changed to look different. For the same reason it
is very difficult to develop a vaccine.

Hepatitis C is considered a blood born disease, and it is thought
that many people with hepatitis C contracted it either through a
blood transfusion or by receiving blood products (gammaglobulin,
plasma, etc.) that were contaminated with hepatitis C, or by sharing
needles with intravenous drug users that were infected with
hepatitis C. Prior to 1990 blood could not be screened for HCV due
to the absence of a reliable test, and therefore people who received
blood products before that year are considered as having been at
risk. Thanks to HCV testing after 1990 the risk of acquiring
hepatitis C from blood transfusion has been reduced to well under
1%.

There are cases of hepatitis C with no evidence of blood to blood
exposure (receiving blood transfusions or products, needle sticks or
needle sharing), where it is unknown how these individuals became
infected.




What is the Natural History of Hepatitis C ?
Natural History of Chronic HCV Infection
New insights into the Natural History of HCV
Hepatitis Time Line
New Hepatitis Guidelines
Natural History of HCV Carriers With Normal Aminotransferase
Really Benign?
Development Conference on the Management of Hepatitis C 2002


Final NIH Consensus Statement
Read the final report recently issued on the NIH Consensus
Development Conference on the Management of Hepatitis C 2002.
This important document will drive current and future
approaches to the management and care of HCV.

http://consensus.nih.gov/cons/116/116cdc_intro.htm

What is the Natural History of Hepatitis C?
The Virus
HCV is an RNA virus of the Flaviviridae family. There are 6 HCV
genotypes and more than 50 subtypes. These genotypes differ by as
much as 30 to 50 percent in their nucleotide sequences. The virus
also has a high propensity to mutate. The lack of a vigorous
T-lymphocyte response appears to promote a high rate of chronic
infection.
The extensive genetic heterogeneity of HCV has important diagnostic
and clinical implications, perhaps explaining difficulties in
vaccine development and the lack of response to therapy. Genotype 1
accounts for 70 to 75 percent of all HCV infections in the United
States and is associated with a poorer response to treatment.
HCV replicates preferentially in hepatocytes but is not directly
cytopathic, leading to persistent infection. During acute infection,
the level of viral genomes/mL of plasma or serum has been reported
to range from 105 to 107. Chronic HCV RNA levels are quite variable
from person to person and generally range from 50,000 to 5 million.
However, within the same individual, RNA levels are relatively
stable.
Epidemiology
According to the National Health and Nutrition Examination Survey
(NHANES) of 1988 - 1994, 3.9 million Americans were infected with
hepatitis C, and of this group, 2.7 million are estimated to have
chronic infection. However, NHANES is a population-based household
survey that largely excludes groups with a substantially increased
prevalence of infection, such as persons who are incarcerated,
homeless, or institutionalized due to mental illness.
Although difficult to assess accurately, the incidence of HCV
infection declined sharply in the late 1980s. Transmission from
blood products was virtually eliminated by the introduction of a
more sensitive test for anti-HCV antibodies in mid-1992. Currently,
approximately 35,000 acute HCV infections are estimated to occur
each year. Because of the high rate of persistent infection, a
fourfold increase in the number of persons with chronic HCV
infection is projected to occur from 1990 to 2015. The prevalence of
HCV is presently believed to be at least 1.8 percent, making HCV the
most common blood-borne infection in the United States. Persons aged
40 to 59 years have the highest prevalence of HCV infection, and in
this age group, the prevalence is highest in African-Americans (6.1
percent).
HCV transmission occurs primarily through exposure to infected
blood. This exposure exists in the context of injection drug use
(IDU), blood transfusion, solid organ transplantation from infected
donors, unsafe medical practices, occupational exposure to infected
blood, birth to an infected mother, multiple heterosexual partners,
and high-risk sexual practices. High HCV seroprevalence rates (from
15 to 50 percent) have been observed in specific subpopulations,
such as the homeless, incarcerated persons, and hemophiliacs, with
the highest rates (70 percent to more than 90 percent) reported in
IDUs.
Acute Infection
After initial exposure, HCV RNA can be detected in blood in 1 to 3
weeks and is present at the onset of symptoms. Antibodies to HCV are
detected by enzyme immunoassay (EIA) in only 50 to 70 percent of
patients at the onset of symptoms, increasing to approximately 90
percent of these patients after 3 months. Within an average of 2 to
8 weeks, liver cell injury is manifested by elevation of serum
alanine aminotransferase (ALT). Acute infection can be severe but is
rarely fulminant. Symptoms are uncommon but can include malaise,
weakness, anorexia, and jaundice. Symptoms usually subside after
several weeks as ALT levels decline.
Chronic Infection
Chronic HCV infection is diagnosed by the detection of HCV RNA at
least intermittently in the blood by either qualitative or
quantitative tests for a period of at least 6 months. In general,
prospective studies have shown that the majority of HCV-infected
persons develop chronic infection. Factors associated with
spontaneous clearance of HCV infection appear to include younger
age, female gender, and certain major histocompatability complex
genes. African-American men appear to be least likely to
spontaneously clear the virus.
The most important sequelae of chronic HCV infection are progressive
liver fibrosis leading to cirrhosis, end stage liver disease (ESLD),
and HCC. Estimates of the proportion of chronically infected persons
who develop cirrhosis 20 years after initial infection have been
substantially higher from retrospective studies (17 to 55 percent)
than from prospective studies (7 -16 percent). The actual risk of
progressive disease at 20 years is now considered to be closer to
the estimates from prospective studies. There is little evidence
that the risk of progression of liver disease is affected
significantly by virologic factors, including viral load, viral
genotype, and quasispecies diversity. However, many host factors are
observed to increase this risk, including older age at time of
infection; male gender; and an immunosuppressed state, such as HIV
infection. Hepatitis B appears to increase the risk of progressive
liver disease.
Alcohol use plays an important role in increasing the risk of
progressive liver disease, with strong evidence for the detrimental
effects of 60 g/day in men (equivalent to six beers, four glasses of
wine, or three mixed drinks) and 40 g/day in women, but there is
suggestive evidence that lower amounts can also increase the risk of
liver damage associated with HCV. Other factors, including iron
overload, nonalcoholic fatty liver disease, schistosomal
coinfection, potentially hepatotoxic medications, and environmental
contaminants, may also have important effects.
In the United States, deaths associated with chronic HCV are
currently more likely to be due to ESLD than to HCC. Data from death
certificates in 1999 found that approximately 4,000 deaths were
attributed to HCV infection, but this is likely to be an
underestimate. The only treatment option for persons who have
developed ESLD (decompensated cirrhosis) is transplantation.
Currently, HCV is the primary reason for liver transplantation in
the United States. Little is known about the clinical course and
risks of HCV-related complications in persons who have been infected
longer than two decades. HCV accounts for an estimated one-third of
HCC cases in the United States. HCC rarely occurs in the absence of
cirrhosis or advanced fibrosis. The incidence of HCV-related HCC is
continuing to rise in United States and worldwide, in part because
of the increasing numbers of persons who have been chronically
infected for decades, the presence of comorbid factors, and the
longer survival of persons with advanced liver disease due to
improved management of complications. Risk factors for HCC in
persons with chronic HCV infection are largely the same as those for
the development of ESLD.
Extrahepatic Manifestations of HCV
Patients with chronic HCV can present with extrahepatic
manifestations or syndromes considered to be of immunologic origin,
such as rheumatoid symptoms, keratoconjunctivitis sicca, lichen
planus, glomerulonephritis, and essential mixed cryoglobulinemia.
Cryoglobulins have been detected in the serum of up to one-half of
patients with chronic HCV, but the clinical features of essential
mixed cryoglobulinemia are less frequent. Chronic hepatitis C is
also related to porphyria cutanea tarda.
06/17/02
Source
NIH Consensus Development Program

Natural History of Chronic HCV Infection:
Introduction:
There are many uncertain issues regarding hepatitis C virus (HCV)
infection, chief among which is the question of its natural history.
Outcome data are needed for two obvious reasons:(1) the need to
inform hepatitis C virus (HCV) carriers of what to anticipate in
their future and, if possible, to reassure them about potential
sequelae, and (2) the need to make rational decisions regarding
treatment with drugs that currently are of only limited therapeutic
value. The problem is compounded by the conflicting views held with
respect to the natural history, some regarding chronic HCV infection
as a universally progressive disease that will inevitably be
responsible for serious chronic liver disease or liver
disease-related demise provided other disease entities do not
intervene first, while others regard it as a progressive disease
limited to a minority of infected individuals, its course dictated
by as yet not fully defined factors that might promote liver disease
progression.
What is recognized is that persons who develop acute HCV infection
rarely recover completely, more than 80% of them remaining
HCV-infected. The result is progression to chronic hepatitis,
generally defined by persistence of serum enzyme abnormalities for
at least six months, advancement in a proportion of instances to
cirrhosis, and culmination among a few in the development of
hepatocellular carcinoma (HCC). What is not well established is the
frequency of these changes, the tempo of advancement, and whether or
not there are existing factors that curb or promote disease
progression.
Basis for Uncertainty Regarding Natural History: The difficulties
inherent in attempting to define the natural history of HCV
infection are numerous. First, a natural history study requires
knowledge of onset of acute disease in order to establish frequency
and rate of progression. Unfortunately, onset of acute HCV infection
is rarely recognized; in 80% or more of instances, persons with
chronic HCV infection do not recall ever having had an illness
resembling acute hepatitis. Second, full knowledge of natural
history must include long-term evaluation of the entire spectrum of
the acute disease, ranging from the mildest to the most severe
forms. Because of the paucity of symptoms in most persons infected
with HCV, those with the milder disease are generally overlooked,
thus biasing outcome data in the favor of those with the more severe
illness. Third, a valid study requires equally intense evaluation of
a non-infected control group. Again, the lack of symptoms inhibits
selection of such a group thus foiling conduct of a case-control
study. Fourth, the extraordinarily indolent nature of the disease
process in chronic hepatitis C coupled with its highly extended
course before sequelae are recognized makes study of the natural
history a daunting task, difficult to accomplish. Indeed, the
natural history of the disease is generally more extended than the
natural history of the clinical investigator. Finally, the disease
course is obviously altered if treatment is instituted. Currently,
it is almost routine to attempt treatment of most persons with
compensated chronic HCV infection. It is these items that have made
study of the natural history of hepatitis C so difficult.
Available data therefore have derived either from relatively short
term prospective studies beginning from onset of acute disease,
mostly transfusion-related, or from study of persons with already
established chronic liver disease.
Follow-Up Studies Beginning with Acute Hepatitis: Most such studies
have not exceeded 10 to 15 years in duration (with the exception of
one which is a 17-year follow-up of an outbreak of HCV infection
induced by contaminated immunoglobulin). This time period is
obviously insufficient since in two retrospective/prospective
studies, one from Japan and one from the U.S.A., progression from
apparent acute to chronic hepatitis was estimated to average 10
years, to cirrhosis, 20 years, and to HCC, 30 years, some developing
HCC 40 to 50 years after the presumed acute infection. Nevertheless,
these studies have yielded useful and important information. In five
prospective studies, clinical symptoms have been noted in about 10%
of cases, histologic cirrhosis in 15% to 20%, and HCC identified in
0.7% to 1.3%. Mortality ranged from 1.6% to 6.0%. In the 17-year
follow-up study of imunoglobulin recipients, outcome was reported to
be benign in the majority of instances; 60% did have moderate enzyme
abnormalities, but only 1.8% had histologic evidence of severe
fibrosis (cirrhosis). These prospective studies thus revealed that
during the first two decades following acute infection,
liver-related morbidity and death is modest in frequency.
Follow-Up Studies Beginning with Already Established Chronic Liver
Disease:
Not surprisingly, in four such studies, two from Japan , one from
the U.S., and one from Australia, far more serious sequelae were
noted. In the two studies from Japan, cirrhosis developed in 30% and
42% respectively, and HCC in 15% and 19%. In the U.S. study, similar
devastating outcomes were identified. Thus, in studies beginning
with already identifiable chronic liver disease, serious sequelae
are common. The problem with such studies is that they are "biased"
in the direction of severe forms of the disease; persons infected
with HCV who have no symptoms - perhaps the bulk of cases - do not
come to the attention of investigators in tertiary care or liver
transplantation centers.
More complete information on natural history, therefore, requires a
long-term, prospective study that starts at the time of acute
infection. Such a study has been progress in the U.S. for the past 8
years, sponsored by the National Institutes of Health (National
Heart, Lung and Blood Institute [NHLBI]).
NHLBI Long-Term Follow-Up Study of Transfusion-Associated Non-A,
Non-B (NANB) Hepatitis:
This study aims to determine both mortality and morbidity among
infected transfusion recipients. The study has incorporated all
persons who developed hepatitis, identified by serial serum enzyme
monitoring, in five transfusion studies that had been performed
between 1968 and 1980, as well as a matched control group consisting
of approximately twice the number of subjects who were transfused
but did not develop hepatitis. The two groups consisted of 568 cases
and 984 controls. Among the cases with an original diagnosis of NANB
hepatitis, 71% were later identified to be anti-HCV reactive by the
2nd generation ELISA.
Mortality was examined after an average of 18 to 20 elapsed years
since transfusion. All-cause mortality was found to be almost
identical between the cases and controls (both+50%) regardless of
whether the cohorts consisted of the entire group of NANB hepatitis
cases or of the hepatitis C cases. Liver-related mortality, derived
from examination of death certificates, was significantly higher
among the cases than the controls (3.2% vs 1.5%).
Morbidity has been determined by recalling all living subjects
(cases and controls) for historical interview, physical examination,
and phlebotomy for biochemical, serologic and molecular biologic
evaluation. Liver biopsy was performed, whenever possible, among
those with biochemically-defined chronic hepatitis. 205 cases and
335 controls were available for analysis, a subgroup of 146 cases
having all original (repository) and follow-up sera available,
permitting paired analysis of the HCV data. Among the main group,
31% of the cases and 4% of the controls in followup had biochemical
evidence of chronic hepatitis while anti-HCV and HCV RNA was found
in 53% of the cases and 6% of the controls. Evaluation of the 146
cases with original and follow-up sera revealed that 104 (71%) were
originally anti-HCV positive and 42, anti-HCV-negative. Followup of
the anti-HCV positive cases showed that one-half remained viremic
and had chronic hepatitis, one-fifth remained viremic without
biochemical evidence of chronic hepatitis, 15% continued to be
anti-HCV positive but negative for HCV RNA and without evidence of
chronic hepatitis, and 10% appeared to have recovered completely
showing no evidence of chronic hepatitis nor of any serologic marker
of the original HCV infection. Among the 42 cases that were
originally anti-HCV negative (as well as negative for all other
viral hepatitis markers), almost all remained HCV-negative in
followup, although 19% had chronic hepatitis as defined by
persisting ALT abnormalities.
Liver biopsies among those with chronic hepatitis revealed the
presence of chronic hepatitis without cirrhosis in 58% of them, and
the presence of cirrhosis in 28%. Correlating the histologic
findings with overt clinical evidence of chronic liver disease
(splenomegaly, thrombocytopenia, prolonged prothrombin time,
ascites, varices), only 5% of those with histologically defined
chronic hepatitis alone had observable clinical findings of chronic
liver disease, none manifesting advanced chronic liver disease,
whereas among those with histologically-established cirrhosis, 70%
had clinical findings, 40% of this group having features of advanced
chronic liver disease. Thus, advanced liver disease could be found
in about 5% of the entire 205 cases in followup, or in 13% of those
with biochemical dysfunction of chronic hepatitis.
These data suggest that during the first two decades after initial
HCV infection, an indolent disease ensues that is associated with
relatively low mortality and relatively low overt clinical
morbidity. However, since those with histologic cirrhosis -
representing nearly a third of those biopsied or about 10% of the
entire case cohort in followup - show features of overt chronic
liver disease of mild to moderate severity, this group seems poised
for progressive worsening as followup extends into the third and
fourth decades after initial infection. Whether those with
histologically-defined chronic hepatitis alone will progress to
cirrhosis with the passage of time remains to be seen.
Further long-term followup of the above groups is required and,
indeed, is in process. In this regard, another study is being
conducted to determine mortality and morbidity among young persons
who were phlebotomized almost 50 years ago and whose resultant blood
samples had been stored in deep freeze over this period of time.
Serologic screening of almost 10,000 stored blood samples has
revealed the presence of HCV seropositivity in some, and they and a
large matched control group are presently being scrutinized for
sequelae.
Predictive Factors for Outcome of Chronic HCV Infection:
Since it seems likely that only a limited proportion of HCV-infected
individuals manifest progressive disease, there is speculation that
there may be definable factors that might be predictive of
progressive disease. Viral-related factors that have been examined
include viral dose, viral genotype, and the presence of
quasispecies. Host factors scrutinized have included the age at the
time of infection, race, gender, and geographic location. Extraneous
influences sought have included co-infection with other viruses,
exposure to viral contaminants, smoking, and concomitant chronic
alcoholism. Of these, the latter has proven to play the most
obviously important role, but further studies are warranted.
References:
1. Alter MJ. Epidemiology of hepatitis C in the West. Sem Liver Dis
1995;15:5-14.
2. Mansell CJ, Locarnini SA. Epidemiology of hepatitis C in the
East. Sem Liver Dis 1995;15:3:15-32.
3. Seeff LB; Natural history of viral hepatitis, type C. Sem
Gastrointestinal Dis 1995;6:20-7.
4. Crowe J, Doyle C, Fielding JF, et al: Presentation of hepatitis C
in a unique uniform cohort 17 years from inoculation (abstr).
Gastroenterology 1995;108:A1054.
http://search.freefind.com/find.html?id=8543868&pid=r&mode=ALL&query=natural+history+of+hcv

Natural History of Hepatitis C
Leonard B. Seeff, M.D.

Introduction
Of the many perplexing issues regarding viral hepatitis, type C,
none is more uncertain and, indeed, more controversial than the
matter of its natural history. Knowledge of outcome of the disease
is critical in order to provide meaningful information to persons
who are chronically infected and in order to make judicious and
prudent decisions regarding treatment.
In the course of the last decade of study of what was initially
referred to as non-A, non-B (NANB) hepatitis, and then more
recently, hepatitis C, it had become clear that the vast majority of
persons who develop acute hepatitis C-perhaps over 80 percent-remain
infected. The consequence of this is progression in many such
individuals from acute to chronic hepatitis, advancement in a
proportion of instances to cirrhosis, ending in the development by
some of hepatocellular carcinoma (HCC). This sequence has been
particularly well-recognized among infected persons in Japan,(1,2)
Italy,(3) and Spain. (4) While similar outcomes have been observed
among persons infected in the United States, the frequency of
termination in end-stage liver disease and particularly HCC has
seemed to be less frequent. This has led to two contradictory
viewpoints, the first being that all or most chronically infected
persons will advance to serious or terminal liver disease if they do
not succumb first to another lethal illness, the second holding the
position that only a limited proportion of infected persons develop
progressive disease, the challenge being to determine which persons
will follow this path and the reason or reasons why. Only by
conducting appropriate long-term natural history studies is it
possible to resolve the conflict.
Such studies have been difficult to perform for the following
reasons: (l) most persons who develop acute hepatitis C do so in the
complete absence of symptoms, thus frustrating the ability to
accurately determine onset and hence duration of disease; (2) the
total lack or paucity of symptoms at onset of the illness hinders
the ability to recognize the full disease spectrum, the focus then
being on those with the more severe forms of the illness; (3) the
lack of symptoms associated with the acute illness precludes the
opportunity to select a noninfected control group to perform
appropriate casecontrol followup studies; (4) treatment is now
commonplace which has the clear potential of altering the natural
history of the disease; and (5) the extremely slow rate of
progression of the disease, ranging from 2 to 4 decades, makes it a
daunting task for any investigator to embark on the necessary
long-term studies. Consequently, most data on natural history have
come from relatively short-term followup studies starting with
disease onset, from studies that begin with already established
chronic liver disease, or from retrospective studies. These
approaches tend to focus attention on the more severe form of the
dlsease while neglecting the milder cases that may not come to
attention, thus creating potential outcome bias.

Prospective Studies Beginning from Disease Onset
Five prospective studies have been reported from the United States
and Europe involving persons with transfusion-associated NANB
hepatitis, predominantly but not exclusively due to hepatitis C
virus (HCV) infection. (5-9) The mean duration of followup was 8-15
years. About 10 percent of study subjects were reported in followup
to have clinical symptoms, histologic cirrhosis was noted in 15-20
percent, and HCC was identified in two of the studies (0.7 percent
and 1.3 percent, respectively). Mortality ranged from 1.6-6.0
percent. These studies, with somewhat small numbers and relatively
short durations of followup, demonstrated an unequivocal but modest
frequency of mortality and morbidity over their limited time
courses.
More benign data come from a study reported from Ireland of
HCV-infection following receipt of HCV-contaminated immunoglobulin
products. (10,11) A followup of 232 infected persons over a 1 7-year
period showed that about one-quarter had mild fatigue, none were
jaundiced or had hepatosplenomegaly, and about 60 percent had modest
enzyme abnormalities. Liver biopsies revealed the presence of
chronic hepatitis, mostly mild, in the majority of instances, only
2.4 percent of them showing early cirrhosis and 1.8 percent showing
severe fibrosis. The authors concluded from these data that there
was minimal evidence of progressive disease.

Followup Studies Beginning with Already Established Chronic Liver
Disease
Among three such studies with mean followup periods of 9-15 years,
cirrhosis was reported to develop in 8 percent, 30 percent, and 42
percent, and HCC in 15 percent and 19 percent. (12-14) The high
frequency of cirrhosis and HCC was noted in the two studies from
Japan. (12,13) It is of more than passing interest that this
strikingly high frequency of HCC among persons infected in Japan may
not be replicated once they move to other countries. In a recent
examination of records in Hawaii over a 25-year period seeking
information on HCC among descendants of Japanese immigrants, 28 HCC
cases were identified, 24 of which had sera available for serologic
evaluation. (15) Fifteen of the 24 had hepatitis B virus markers,
while none had HCV markers. This implies that there is either an
extremely low prevalence of HCV in Hawaii, or that another
factor-cultural, nutritional, environmental-exists in Japan that
helps promote carcinogenesis among HCV carriers residing in that
country.
Two other important studies must be considered in the context of
evaluating the natural history of those with already existing
chronic hepatitis C. In one from Japan, involving a followup of
transfusionassociated chronic NANB/C hepatitis cases, HCC
development was found to be common. (16) Attempting to establish the
rate of progression by extending information back to the time of
initial infection based on transfusion histories, the investigators
estimated that chronic hepatitis emerges after 10 years, cirrhosis
after 21.2 years, and HCC after 29 years. In three cases, the
interval even exceeded 50 years. In a similar study from the United
States, involving an initial and followup evaluation of 131
transfusionassociated cases of chronic hepatitis C, initial
evaluation revealed fatigue among 67.2 percent, hepatomegaly among
67.9 percent, histologically-defined "chronic active hepatitis" in
22.9 percent, and HCC in 5.3 percent. (17) During the followup
period of 3.9 years, an additional 5.3 percent developed HCC, and
15.3 percent died. Emulating the Japanese study, the investigators
estimated that, following acute infection, chronic hepatitis could
be identified 13.7+10.9 years later, chronic active hepatitis
18.4+11.2 years later, cirrhosis 20.6+10.1 years later, and HCC,
28.3+11.5 years later. These studies demonstrated two important
points: (l) serious outcomes are common in studies that begin with
already established endstage or near-endstage chronic liver disease;
and (2) the rate of progression is exceptionally slow, serious
sequelae generally beginning to emerge only in the third or later
decades after initial infection. Therefore, satisfactory information
regarding the natural history of chronic hepatitis C can come only
from longer-term prospective studies.

The National Heart, Lung, and Blood Institute (NHLBI) Long-Term
Followup Study of Transfusion-Associated NANB Hepatitis
A long-term followup study has been in progress during the past 8
years directed at evaluating the sequelae of acute NANB hepatitis
that had developed among persons participating in five separate
transfusion studies conducted in the United States between 1968 and
1980. (18) In all five studies, hepatitis had been sought by
prospective, repetitive serum enzyme monitoring of blood recipients,
thus identifying even the entirely subclinical cases. Over 90
percent of these cases were defined as NANB hepatitis, 71 percent of
whom were established to be HCV in origin. A total of 568 hepatitis
cases were identified and matched with a transfused, non-hepatitis
control group (984 subjects) from the same studies, both cohorts
then being subjected to long-term followup evaluation.
All-cause mortality after an average of 18 years of followup was
approximately 50 percent in both the cases and the controls,
indicating no difference between cases and controls. Liver-related
mortality, based on death certificate analysis, was 3.2 percent for
the cases and 1.5 percent for the controls, a difference that was
significant even though the frequency was quite low. Of note is that
71 percent of the study subjects who had died as a consequence of
liver disease were found after enrollment to be heavy drinkers, some
with hospitalizations for this problem. Evaluation of mortality by
life-table analysis at the end of 20 years continued to demonstrate
no difference on mortality between cases and controls. Furthermore,
no difference in mortality could be found when the analysis was
restricted to the HCVpositive cases and their controls.
Morbidity is also being assessed by recalling all living patients to
determine their current status clinically, biochemically,
serologically, and histologically. Two hundred and five cases and
335 controls were available for analysis, with a subgroup of 146
cases among whom all original (repository) and followup sera were
available, permitting paired comparisons. Among the main group,
certain marked differences were found between cases and controls.
This included the frequency of fatigue and hepatomegaly, both found
to be present slightly more commonly among cases than controls, the
presence of raised serum enzymes (noted in one-third of cases and 4
percent of controls), and the presence of HCV-related hepatitis
serology (anti-HCV and HCV RNA in 53 percent of cases and 6 percent
of controls). Focusing on the 146 with available original and
followup sera, 104 (71 percent) of them could be shown to have
originally developed acute HCV-related transfusion-associated
hepatitis. In followup of these individuals, one-half remained HCV
RNA-positive in association with biochemical evidence of chronic
hepatitis; one-fifth remained HCV RNA-positive but without
biochemically defined chronic hepatitis; 15 percent showed anti-HCV
alone, and 10 percent appeared to have recovered completely, both
biochemically and seologically. Followup of the originally
HCV-negative cases revealed that 93 percent remained negative, but
19 percent showed chronic hepatitis of undefined etiology.
Liver biopsies revealed the histology of chronic hepatitis alone in
58 percent and of cirrhosis in 28 percent. Correlating the
histologic findings with overt clinical evidence of chronic
hepatitis, clinical disease could be identified in 5 percent of
those with chronic hepatitis alone, but in 70 percent of those with
cirrhosis. However, among the latter, only about one-third of those
with evident chronic liver disease had clearly advanced or
moderately advanced chronic liver disease. Thus, 15-18 years after
the initial infection, advanced liver disease could be demonstrated
in 5-8 percent of the entire living cohort of NANB hepatitis cases
among whom followup could be accomplished, or in 13 percent of those
who had been defined biochemically to have chronic hepatitis. These
data suggest that, at this juncture in the followup of the
transfusion-associated NANB/C hepatitis cases, both mortality and
severe morbidity are present, but in relatively low frequency.
Moreover, overt morbidity appears confined largely to those with
histologically identified cirrhosis. Whether persons with
histologically detected chronic hepatitis alone will ultimately
advance to cirrhosis and then assume the risks of the cirrhotic
group remains to be determined through continued followup.
Another long-term followup study is also in progress that involves
approximately 10,000 young Air Force recruits who were phlebotomized
between 1948 and 1954 in the course of the evaluation, at that time,
of an outbreak of streptococcal infection. The samples had been
stored in deep freeze for the past 40-45 years. With their
rediscovery, the entire group was tested for the presence of HCV
markers. A number of positive samples having been identified, a
mortality and morbidity study is now in progress, comparing outcome
among those who are positive with those selected as negative
controls. This represents a unique opportunity to determine outcome
among young persons found to be HCV-positive almost 50 years ago.
Data will be presented.

Predictive Factors for Outcome of Chronic HCV Infection
If progression of chronic HCV infection is not inevitable, is it
possible to identify factors that might help in predicting outcome?
Viral factors that have been examined include viral dose, genotype,
and the presence of quasispecies, each of which have been identified
as having predictive value, although available data are conflicting.
(19-24) Host-related factors include age, race, gender, and
geographic location. Age may play an important role, the rate of
progression appearing to be more rapid as the age at the time of
infection rises. Geographic location also may be of importance,
perhaps related to cultural or environmental differences. Extraneous
influences may consist of co-infection with other viruses, exposure
to environmental contaminants, smoking, or concomitant chronic
alcoholism. Co-infection with hepatitis B has been reported to
increase the severity of chronic hepatitis C and the likelihood of
development of HCC. (25) Co-infection with HIV has been shown in
hemophiliacs to increase HCV RNA levels(26) and to worsen the course
of the disease. (27) Co-infection with hepatitis G was earlier
considered likely to play a promoting role in disease progression,
but careful studies have recently disproved these views. (28,29)
Chronic alcoholism quite clearly enhances disease progression,
either because it promotes increased viral replication or because it
is an additive liver-damaging factor. (30,31) The use of alcohol
should be strongly condemned in persons who have chronic HCV
infection.

Summary
It is quite clear that a proportion of persons with chronic HCV
infection will advance in time to cirrhosis and progress eventually
to terrninal chronic liver disease, in some instances after
developing HCC. These are the seriously ill patients seen in
tertiary care and liver transplant centers. The perception of the
frequency of these adverse events depends, in part, on the stage of
the disease at the time that followup studies are initiated. If they
begin when chronic liver disease has already evolved, the frequency
and tempo of progression is found to be high, particularly in some
geographic areas such as Japan and Italy. If, however, studies begin
with disease onset, serious sequelae seem to be defined less
frequently. Current data suggest that during the first two decades
after infection, with occasional exceptions, the disease runs an
indolent course with relatively low frequencies of mortality and
overt morbidity. If cirrhosis has developed during this period,
symptomatic disease is more common than is noted when the histology
demonstrates chronic hepatitis without cirrhosis. It can be
anticipated that future morbidity and liver-related mortality is
likely to emerge predominantly from the group that has developed
cirrhosis, and this will become apparent as the disease process
moves into its third or later decades. Whether progression is
enhanced by definable factors is not yet fully established, but it
does appear that late age of infection, genotype characteristics,
and concomitant alcoholism may play promoting roles. Other promoting
factors must continue to be sought. Whether persons with histologic
evidence of chronic hepatitis alone at the end of the second decade
will ultimately advance to cirrhosis and then assume the increased
risks that accompany that lesion needs further evaluation through
additional long-term studies. The proportion of cases whose disease
remains completely stable is not yet known but might well represent
the bulk of cases. The problem at present is that while helpful
aggregate data are beginning to emerge, prediction of outcome for
the individual case remains difficult to define. Indeed, the need
for this information would be reduced if available treatment were
more effective, less uncomfortable, and less costly. Continued
long-ter n studies both of natural history and treatment strategies
are, therefore, sorely needed. Finally, there is critical need for
natural history and treatrnent studies involving children and
adolescents with chronic HCV infection because of the extended life
that awaits them.





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and histopathological followup of chronic post-transfusion
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New insights in to the natural history of hepatitis C
virus infection


Health Research Board & Cork University Hospital

Liam Fanning
A viral version of the 'invasion of the body snatchers' - the
Hepatitas C virus invades the human liver.

Chronic hepatitis C infection is a ubiquitous disease, affecting
over 200 million people worldwide. The hepatitis C virus (HCV) is
spread by exposure to infected blood or blood products. The most
striking feature of hepatitis C virus infection is the tendency
toward chronicity. The human leukocyte associated antigen (HLA) is a
host-encoded protein that presents bacterial and viral proteins to
the infected individual's immune system. The HLA has been shown to
influence host response to the HIV and the hepatitis B virus.

Researchers at the Hepatitis C Unit, Cork, Department of Medicine,
Cork University Hospital, have assessed the likely influence of host
HLA on the ability of infected individuals to eliminate the HCV. The
study population was infected from a single source, with a single
type of the hepatitis C virus, and the year of infection was known
for each individual. The study population was equally divided
between those who had evidence of exposure to the HCV, but who had
cleared the virus, and those who were persistently infected with the
virus.

In a series of experiments, DNA was isolated from the blood of these
individuals. Their genetic profile was determined molecularly at two
specific locations on chromosome 6. Analysis of this genetic data
revealed that presence of a particular HLA group was associated with
a greater likelihood of clearance of the hepatitis C infection.
Additional analysis identified a HLA gene, which was associated with
persistent hepatitis C infection in this study population. Evidence
from the study may lead to the identification of crucial protein
segments from the HCV important for immune system mediated
clearance.

Chronic hepatitis C is characterized by persistent viraemia (i.e.
the continuous presence of detectable virus), the natural variation
of which is undefined. Researchers at the Hepatitis C Unit have
evaluated the amount of virus present in the blood over an extended
period of patient follow-up and developed a model for predicting
change in viral load over time in their study population. The
results of this research suggest that viral load appears to increase
over time in the chronically infected individual. This model, which
is currently undergoing prospective evaluation, may enable the
prediction of when chronically infected individuals are likely to
have a serum viral load correlated with likely response to
anti-viral therapy.

The ongoing goal of the Hepatitis C Unit is to define the viral and
host factors that influence the natural progression of hepatitis C
virus infection.



Contact: Liam Fanning PhD,
Hepatitis C Unit, Department of Medicine, Clinical Sciences
Building,
Cork University Hospital;
Tel: +353-21-901281; Fax: +353-21-345300
http://www.irishscientist.ie/2000/contents.asp?contentxml=036Bs.xml&contentxsl=insight3.xsl

Hepatitis Time Line

2000 B.C. First recorded references to hepatitis epidemics.

1947 F.O. MacCallum, using human volunteers, differentiates
hepatitis A, which is spread by contaminated food and water, from
hepatitis B, which is spread by blood.

1963 Baruch Blumberg and Harvey Alter discover Aa, the Australian
antigen (later called HBsAg).

1967-1968 Blumberg, Kazuo Okochi, Alfred Prince, Alberto Vierrucci,
and colleagues report that Aa is involved in the development of
hepatitis B.

1969 Irving Millman and Blumberg devise a concept and through the
Fox Chase Cancer Center receive a patent for using Aa to prepare a
hepatitis B vaccine.

1970 D. S. Dane discovers whole hepatitis B virus particles in blood
samples examined with the electron microscope.

1972 Laws are passed in the United States requiring testing of donor
blood for HBsAg antigen.

1973-1974 Stephen Feinstone and colleagues and Maurice Hilleman and
colleagues discover and describe hepatitis A virus.

1975 Wolf Szmuness and Hilleman and colleagues begin tests of the
hepatitis B vaccine.

1977 Mario Rizzetto and John Gerin discover hepatitis D.

1980-1981 Subunit hepatitis B virus vaccine derived from blood serum
is developed by Hilleman and colleagues, proved effective and
licensed for general use.

1983 Mikhail Balayan describes the hepatitis E virus.
Hepatitis time Line

1983-1986 Subunit hepatitis B virus vaccine derived from yeast is
developed by William Rutter and colleagues and approved for use.

1989 Daniel Bradley provides Chiron with non A-non B hepatitis serum
from chimpanzees; Michael Houghton and colleagues discover a single
virus, publish the genetic sequence of the viral agent, and change
the name to hepatitis C.

1990 Blood screening for hepatitis C begins.

1996 The first hepatitis A vaccine, made by Merck, is licensed for
general use; another hepatitis A vaccine, developed by SmithKline
Beecham, is proved to be effective

New Hepatitis Guidelines
The National Medical Association (NMA), in a concerted effort to
help eliminate hepatitis in the African-American community, has
issued new guidelines for the prevention and treatment of viral
hepatitis.
According to Dr. Lucille C. Norville Perez, president of the NMA in
Washington, DC, the guidelines "coincide with the Department of
Health and Human Services' Healthy People 2010 initiative, which is
committed to the elimination of disparities in healthcare."

The guidelines address four key efforts: universal vaccination,
increased education, advocacy, and ongoing surveillance and research
to eradicate the disease.

Dr. Perez noted that African Americans have a significantly higher
prevalence of hepatitis B and C than whites do. The chronicity of
these two diseases, and the mortality rates attributed to them, are
also higher.

Part of the reason for this is because African Americans are
typically diagnosed later than whites, Dr. Perez said. "There are
also all the other things impacting their lives that put them at
risk for more rapid progression," she told Reuters Health, which
include drinking, other insults to the liver, poor nutrition,
poverty, and overall worse health status.

Dr. Joanna Buffington, of the Centers for Disease Control and
Prevention in Atlanta, highlighted other reasons for the
disproportionate effect of hepatitis B and C on African Americans.
"Access to vaccinations has not been equitable. Also, blood
transfusions before 1990 were a risk factor, and African Americans
tend to have more transfusions because of such illnesses as sickle
cell anemia."

She added that African-American infants are less likely to be
vaccinated against hepatitis B than infants in other ethnic groups.
"This doesn't get highlighted often," Dr. Buffington said in an
interview with Reuters Health, "but if a mother is chronically
infected, about 90% of infants who aren't immunized will themselves
develop chronic hepatitis B."

Immigrants from Africa and Asia have high rates of hepatitis B, the
CDC researcher added. "Another problem is that African Americans are
more likely to be infected with the type of virus--genotype 1--that
is the hardest to treat. The rate of infection with genotype 1 is
about 90% in the African-American population, versus 70% in the
general population."

"We want to see vaccinations made available for young adults," Dr.
Perez emphasized. "Because of the increased sexual activity and drug
activity between the ages of 18 and 34, having it associated with
admission to college, or as a requirement for job placement as we do
with tuberculosis screening, would be appropriate."

Is the Natural History of Hepatitis C Virus
Carriers With Normal Aminotransferase Really
Benign?

Hepatology December 2001 o Volume 34 o Number 6
Vincent Di Martino et al
This comes from one of the best sites on
Hepatitis C and HIV
http://www.natap.org/

editorial note: several studies have reported
that on HCV/HIV coinfected patients a percentage
of patients with normal ALT have more progressed
liver disease. A number of studies show & it is
generally accepted that HIV can accelerate HCV
progression for many coinfected persons.

Dear Sir:

We read with interest the article by Persico et
al. (1) concerning the histological evolution of
hepatitis C virus (HCV) carriers with
persistently normal alanine aminotransferase
(ALT) values. This is a poorly characterized
condition, which is likely to occur in a
significant proportion of subjects with
community-acquired infection, and which is
generally thought to progress either extremely
slowly or not at all to more severe forms of
chronic liver disease.(2,3) The reasons for this
seemingly benign and indolent course of li ver
disease, which will probably never require
antiviral treatment, are largely unknown,
although previous studies reported an
association with a specific genetic
background,(4,5) a strong cell-mediated immune
response to HCV polypeptides,(6,7) and infection
with HCV type (2.2,8)

We also had an opportunity to follow a cohort of
118 blood donors (68 males, median age 52 years,
range, 18-69 years) with persistently normal ALT
who were rejected from donation on serological
detection of anti-HCV. Ninety-four (80%)
reported known risk factors for HCV infection
(transfusion, surgery), whereas in 24 (20%) no
risk factors could be identified. Eighty
patients (68%) were HCV RNA-positive by
reverse-transcription nested polymerase chain
reaction, and 47 (78%) of the 60 patients
tested, were infected by genotype 2a/c, 11 (18%)
by genotype 1b, and 2 (3%) by genotype 1a (Inno
LiPA, Innogenetics, Gent, Belgium). Sixty-two
(52.5%) of the 118 subjects were progressively
lost to follow-up over a period of 7 years and,
of these, only 3 had occasional ALT fluctuations
(determined at least 4 times per year) while on
follow-up. The reason for drop-out was
predominantly demotivation, as 35 of the 38
initially HCV RNA-negative subjects belonged to
this group. Fifty-six anti-HCV positive patients
are still regularly attending our outpatient
clinic for long-term follow-up, the current
median being 7 years (range, 5-8 years). Of the
53 initially HCV RNA-positive subjects in this
group, 40 still have persistently normal ALT, 9
show occasional minor fluctuations, whereas 4
have developed sustained ALT elevations. Two of
the latter underwent biopsy and were
subsequently treated with antiviral therapy.
Eight (15%) of the 53 subjects spontaneously and
permanently lost HCV RNA after 3 to 7 years of
follow-up. A liver biopsy was performed in 33
HCV RNA-positive patients (all with persistently
normal ALT) after informed consent had been
given and repeated in 18 patients 4 to 7 years
(median, 6 years) later. As illustrated in
Figure 1, histological grading remained
unchanged in the majority of patients during a
follow-up comparable to or greater than that of
Persico et al.(1) with definite deterioration
occurring in 3 patients in whom a significant
(>2 points in score) progression of fibrosis was
observed. One HCV RNA-positive patient, in whom
liver biopsy showed mild chronic hepatitis at
baseline, developed hepatocellular carcinoma
(HCC) in well-compensated cirrhosis after 5
years of follow-up, despite persistently normal
ALT. The tumor was discovered as part of an
ultrasound screening program as a single nodule
of 5 cm and was successfully treated by
radio-frequency thermal ablation. The patient is
alive and well 2 years after the procedure
without recurrence of the disease.

We believe that several specific points should
be emphasized. Firstly, the duration of
histological follow-up in Persico's study is far
too short to draw conclusions on the natural
history of chronic HCV infection in this
peculiar patient category, since some patients
may have an accelerated progression of fibrosis.
Secondly, such prospectively followed cohorts
may hide occasional patients with biochemically
silent liver disease evolving to cirrhosis and
HCC which may be overlooked unless a careful
screening program is implemented. Thirdly, a
considerable proportion of these patients may
eventually clear HCV infection. This phenomenon
is generally thought to be anecdotal9 or
questionable, although our study does prove
that, under certain circumstances, HCV infection
may spontaneously disappear after several years,
at least in this clinical setting.

AGOSTINO CIVIDINI
CHIARA REBUCCI
ENRICO SILINI
MARIO U. MONDELLI
Department of Infectious Diseases and Pathology
IRCCS Policlinico San Matteo
University of Pavia
Pavia, Italy
REFERENCE 1

GASTROENTEROLOGY 2000;118:760-764

tural History of Hepatitis C Virus Carriers
With Persistently Normal Aminotransferase Levels


MARCELLO PERSICO, ELIANA PERSICO, ROSALBA
SUOZZO, SALVATORE CONTE, MASSIMILIANO DE SETA,
LEONARDO COPPOLA, BRUNO PALMENTIERI, FERDINANDO
CARLO SASSO, and ROBERTO TORELLA

Internal Medicine and Hepatology Unit, II
University of Naples, Naples, Italy

Background & Aims: Some patients with serum
hepatitis C virus (HCV) have persistently normal
aminotransferase (ALT) levels and are affected
by cirrhosis. This study prospectively evaluated
progression of the disease in a group of
anti-HCV-positive patients with persistently
normal ALT levels.

Methods: Thirty-seven subjects were studied.
Each subject underwent liver biopsy at baseline
and after 5 years of follow-up. At baseline,
serum samples were tested for genotypes and HCV
RNA load. ALT levels and serum HCV RNA were
tested every other month and every 6 months,
respectively. Patients with increased ALT were
discharged from the study and treated with IFN.
Five years after the end of IFN therapy, a liver
biopsy was performed.

Results: Liver biopsy at baseline showed chronic
hepatitis in 34 patients and normal histology in
3 patients, 2 of whom were negative for HCV RNA
and 1 positive.

HCV genotypes were distributed as follows: 2a,
56%; 1b, 41%; and 1a, 3%. At the end of 7-year
follow-up, 73% of the patients still had normal
ALT values. Liver histology after 5 years was
comparable to that observed at entry to study.
Conclusions: Most patients with persistently
normal ALT serum levels have very mild chronic
hepatitis. However, healthy anti-HCV-positive
subjects exist. In patients with HCV-related
chronic hepatitis associated with persistently
normal ALT levels, the grade of disease activity
does not increase over years and progression to
cirrhosis is slow or absent.