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Is the Natural History of Hepatitis C Virus Carriers With
Normal Aminotransferase Really Benign?
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Hepatology December 2001 o Volume 34 o Number 6
Vincent Di Martino et al
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
Natural 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.
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