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Statistics and meaning of
normal ALTs with Hepatitis C Virus+....
(WebMD), 8/28/01 7:31 p.m.
This article contains discussion of several published
studies which look at Hepatitis C Virus positive individuals with normal
ALTs (liver function test) and the relationship between ALT
levels and Hepatitis C Virus disease progression. Whether or not such
individuals should initiate Hepatitis C Virus treatment is discussed.
Natural History of Hepatitis C Virus Carriers With
Persistently Normal Aminotransferase Levels
Persico M, Persico E, Rosalba S, Conte S, De Seta M,
Coppola L, Palmienteri B, Sasso FC, and Torella R Internal
Medicine and Hepatology Unit, II University of Naples, Naples,
Italy GASTROENTEROLOGY 2000;118:760-764
Abstract
Background & Aims:
Some patients with serum hepatitis C virus (Hepatitis C Virus) have
persistently normal aminotransferase (ALT) levels and are
affected by cirrhosis. This study prospectively evaluated
progression of the disease in a group of anti-Hepatitis C Virus-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 Hepatitis C Virus RNA
load. ALT levels and serum Hepatitis C Virus 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 Hepatitis C Virus RNA and 1 positive. Hepatitis C Virus 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-Hepatitis C Virus-positive
subjects exist. In patients with Hepatitis C Virus-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.
Introduction:
Many subjects with hepatitis C virus (Hepatitis C Virus) infection have
persistently normal aminotransferase (ALT) levels and are
considered asymptomatic anti-Hepatitis C Virus carriers. Most of these
patients have been documented to have some degree of
histologically proven chronic liver damage ranging from mild
chronic hepatitis to liver cirrhosis (6). Hepatitis C Virus genotype
distribution and viral load have also been explored, and
available data in literature are still conflicting.
Several studies suggest that these patients do not benefit
from interferon treatment. However, no data are available on
the natural history of chronic hepatitis C associated with
persistently normal ALT levels that support this observation.
In particular, whether there is any progress in grading and
staging of chronic hepatitis in these patients is not known.
This study was therefore designed to evaluate the natural
history of a group of anti-Hepatitis C Virus-positive patients with
persistently normal ALT levels during 7 years of prospective
follow-up to provide further insights into the concept of
disease progression. We found that patients with persistently
normal ALT levels have chronic hepatitis whose grade of
activity does not increase over 5 years of observation. This
lends support to the concept that these patients may not
benefit from interferon treatment.
Discussion:
Most patients infected with Hepatitis C Virus have different degrees of
liver damage that can worsen and lead to liver cirrhosis in
20% of the cases, although subjects with normal liver
histology despite ongoing Hepatitis C Virus viremia have been documented.
However, the long-term natural history of the so-called
asymptomatic carriers of Hepatitis C Virus is not clear. In general,
although ALT levels do not relate to the entity of the liver
damage, patients with persistently normal ALT levels have less
severe disease. Supporting these data, Mathurin et al. (21)
recently showed in a large cohort of patients that those with
normal ALT had less severe fibrosis than those with increased
ALT. Nevertheless, some reports show the presence of cirrhosis
in such patients. Whether these patients should be treated
with interferon is still subject to debate (14).
This study was designed to evaluate whether Hepatitis C Virus-infected
subjects with persistently normal ALT levels have any
progression of liver damage after 5 years of follow-up. This
might be helpful in deciding whether these patients need to be
treated with interferon. The prospective follow-up supports
the concept that all Hepatitis C Virus-positive patients with persistently
normal ALT levels have chronic hepatitis with slow
progression, or no progression at all, to more severe liver
disease (i.e., cirrhosis). The first consequence of this might
be the inefficacy of interferon therapy in asymptomatic
patients in favor of a wait-and-see approach. This is similar
to data from a recent study of interferon treatment in
asymptomatic patients14 concluding that such treatment is not
effective in these patients. Nevertheless, interferon is
suggested as a therapeutic choice for patients with mild
disease and flaring ALT. The question is whether and when
interferon should be a therapeutic option. In our study, no
patients had increases in ALT values after the fourth year of
follow-up. Possibly because of the accurate follow-up of such
patients, we
selected a very strict group of subjects who really
represent "asymptomatic" carriers of Hepatitis C Virus.
Interestingly, patients with increases in ALT levels did not
have the worst histological score, suggesting that ALT levels
are not a valuable predictor of progression of disease. Most
of these subjects( 6,7) treated with interferon did not
benefit from the therapy, and the histological score 5 years
after the end of interferon treatment showed progression to
cirrhosis in 1 patient and mild progression of fibrosis in 2
patients. Only 1 patient responded to therapy; his histology
improved from mild chronic hepatitis to minimal liver changes.
A recent demonstration of a lower degree of fibrosis in
patients with persistently normal ALT activity (21) supports
the concept of very slow progression, if any, of liver disease
in these subjects. However, whereas Mathurin et al. (21)
evaluated progression of liver fibrosis over a virtual period
of time of assumed years before biopsy, our data instead
strongly demonstrate a lack of progression of disease activity
in 2 liver biopsies performed several years apart in a
prospective designed study.
The diversion of the 2 groups (asymptomatic and
symptomatic), at the beginning of the study under the same
name, may suggest that the pathological potential of Hepatitis C Virus is
expressed only in a particular genetic background. The immune
system of "asymptomatic Hepatitis C Virus carriers" might be able
to satisfactorily react to the turnover of the quasi species,
avoiding the escape mechanism.
The mean value of the apparent duration of the disease
(determined only in a small sample and still under observation
at the time of second biopsy) was about 10 years. This, added
to the 5 years of follow-up, represents a long period of
observation to draw conclusions on the natural history of the
disease in these patients. Nevertheless, a longer follow-up
might be needed.
The indifferent Hepatitis C Virus genotype distribution together with the
lack of association of any particular Hepatitis C Virus genotype, with a
more or less pronounced disease progression, confirms our and
other investigators' observations; and seems to rule out the
possibility that the state of asymptomatic carriers of Hepatitis C Virus
might be mainly determined by a more or less aggressive Hepatitis C Virus
genotype.
Through initial screening of anti-Hepatitis C Virus-positive patients, we
recognized 2 patients who were Hepatitis C Virus RNA negative and who had
normal liver histology. These patients never showed positivity
for Hepatitis C Virus RNA. They might have recovered from the acute disease
showing a permanent immunity (anti-Hepatitis C Virus positive). One patient
who was persistently positive for Hepatitis C Virus RNA also had no signs of
liver disease at biopsy, thus confirming that true
"healthy carriers" of Hepatitis C Virus may exist. In conclusion,
this study suggests that the majority of asymptomatic carriers
of anti-Hepatitis C Virus have histological features of very mild chronic
hepatitis. In these patients with more than 5 years of
observation, the disease does not worsen, supporting the
concept that the natural history of chronic hepatitis in this
group of subjects is characterized by very slow or no
progression at all to more severe grades of evolution. This
supports the useless approach with interferon therapy in these
patients. Data also show that anti-Hepatitis C Virus carriers, along with
subjects with chronic hepatitis and Hepatitis C Virus healthy carriers, may
represent subjects who healed after Hepatitis C Virus infection. A very
strict follow-up with frequent ALT level determinations is
suggested in these patients to recognize subjects only
apparently "asymptomatic" for making appropriate
therapeutic decisions.
(6) Clinical, histological, and virological features of
hepatitis C virus carriers with persistently normal or
abnormal alanine transaminase levels
Puoti C, Magrini A, Stati T, Rigato P, Montagnese F, Rossi
P, Aldegheri L and Resta S Hepatology, Vol 26, 1393-1398
This study was aimed to evaluate demographic, clinical,
histological, and virological characteristics of 46 hepatitis
C virus (Hepatitis C Virus) carriers with persistently normal alanine
transaminase (ALT) levels and to compare the results with
those obtained in a group of 52 Hepatitis C Virus-RNA- positive patients
with elevated ALT levels. Subjects with normal ALT were more
often females (P < .001), were more likely to be
asymptomatic (P < .001), and have a lower incidence of risk
factors for Hepatitis C Virus transmission (P < .01). All patients with
normal ALT had significant histological liver damage. The mean
grading and staging did not differ between patients withnormal
and those with raised ALT concentrations. Moderate to severe
hepatitis was more frequently found among subjects with normal
than with elevated ALT. Hepatitis C Virus genotype 2a was far more common in
subjects with normal (43%) than with abnormal ALT levels (6%;
P < .002), genotype 1b being more frequent in these latter
(50% vs. 17%; P < .001). Patients with normal ALT levels
had similar serum Hepatitis C Virus-RNA titers than subjects with raised
ALT. Neither Hepatitis C Virus genotype distribution nor viral load
correlated with the severity of liver damage. We conclude that
significant liver disease may occur irrespective of clinical
symptoms, ALT levels, Hepatitis C Virus genotypes, and viral load.
(14) Interferon Alfa Treatment of Hepatitis C Virus RNA Carriers With
Persistently Normal Transaminase Levels: A Pilot Randomized
Controlled Study
Sangiovanni1 A, Morales R, Spinzi GC, Rumi MG, Casiraghi A,
Ceriani R, Colombo E, Fossati M, Prada A, Tavani E, and Minoli
G HEPATOLOGY, March 1998, p. 853-856, Vol. 27, No. 3
Most patients with serum hepatitis C virus (Hepatitis C Virus) RNA and
persistently normal alanine transaminase (ALT) levels show
histological features of mild to moderately active chronic
hepatitis. Some cirrhosis has also been reported. To assess
whether interferon (IFN) treatment led to long-term Hepatitis C Virus
suppression in these patients, 31 previously untreated
patients (15 men, 16 women; mean age, 44 years) with serum Hepatitis C Virus
RNA, persistently normal ALT levels on at least four
consecutive occasions 2 months apart, and histological
features of chronic hepatitis (21 mild activity, 10 moderate
activity) were randomized to receive IFN--2a, 3 MU three times
a week for 6 months (n = 16), or no treatment (n = 15). All
patients were followed up for at least 6 months after
treatment ended. Hepatitis C Virus RNA was tested by nested
reverse-transcription polymerase chain reaction (RT-PCR) using
5'-untranslated region complementary primers, quantified by
branched-DNA assay, and typed by nested RT-PCR testing for the
Hepatitis C Virus core region. Treated and untreated patients had similar
epidemiological, virological, and histological
characteristics. At the end of treatment, serum Hepatitis C Virus RNA was
still detected in 15 patients (94%) and 14 controls (93%). ALT
levels flared up in 10 patients receiving IFN (62%) and in 1
control (62% vs. 7%; P < .005, 2 test). In conclusion, 6
months' treatment with IFN--2a did not eradicate Hepatitis C Virus RNA from
serum in carriers with persistently normal ALT levels but
caused ALT flare-ups in two thirds of them. Until more is
known about the natural history of Hepatitis C Virus RNA carriers with
normal ALT levels, these patients should not be treated with
IFN.
(21) Slow Progression Rate of Fibrosis in Hepatitis C Virus
Patients With Persistently Normal Alanine Transaminase
Activity
Mathurin P, Moussalli1 J, Cadranel JF, Thibault V,
Charlotte F, Dumouche P, Cazier A, Huraux JM, Devergie B,
Vidaud M, Opolon P, and Poynard T HEPATOLOGY, March 1998, p.
868-872, Vol. 27, No. 3
In hepatitis C virus (Hepatitis C Virus) patients with persistently
normal alanine transaminase (ALT), the progression rate of
fibrosis is unknown. The aims of this study were: 1) to
compare Hepatitis C Virus patients with normal ALT (group I) with Hepatitis C Virus
patients with elevated ALT (group II) matched on independent
factors associated with fibrosis; and 2) to assess the
progression rate of fibrosis. One hundred two Hepatitis C Virus patients
were included in each group. Histological lesions were staged
using the METAVIR score. We defined fibrosis progression per
year as the ratio of the fibrosis stage in METAVIR units to
the duration of infection. In group I, ALT values were normal,
and lower than in group II (25 vs. 127 IU/L; P < .0001).
Hepatitis C Virus RNA was present less frequently in group I (66% vs. 97%; P
< .0001). There were no significant differences for viremia
and genotypes. Histological activities were lower in group I
(0.6 vs. 1.38; P < .0001). The stage of fibrosis was lower
in group I (0.95 vs. 1.8; P < .001). The median progression
rate of fibrosis was lower in group I (0.05 vs. 0.13; P <
.001). In group I, after exclusion of negative Hepatitis C Virus-RNA
patients, the median progression rate of positives remained
lower (0.05 vs. 0.13; P < .001). In group I, all cirrhotic
patients (n = 3) were heavy drinkers. Hepatitis C Virus patients with normal
ALT showed weaker histological activity and lower fibrosis
scores, and the progression rate of fibrosis was twice as slow
as in Hepatitis C Virus patients with elevated ALT. In these patients,
severe fibrosis was associated with high alcohol consumption.
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