article contains discussion of several published studies which look at HCV
positive individuals with normal ALTs (liver function test) and the relationship
between ALT levels and HCV disease progression. Whether or not such individuals
should initiate HCV treatment is discussed.
History of Hepatitis C Virus Carriers With Persistently Normal Aminotransferase
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
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.
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.
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.
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.
subjects with hepatitis C virus (HCV) infection have persistently normal
aminotransferase (ALT) levels and are considered asymptomatic anti-HCV 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). HCV genotype distribution and viral load have also been
explored, and available data in literature are still conflicting.
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.
study was therefore designed to evaluate the natural history of a group of anti-HCV-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
patients infected with HCV 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 HCV viremia have been documented.
However, the long-term natural history of the so-called asymptomatic carriers of
HCV 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).
study was designed to evaluate whether HCV-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
HCV-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
a very strict group of subjects who really represent "asymptomatic"
carriers of HCV. 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.
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
HCV is expressed only in a particular genetic background. The immune system of
"asymptomatic HCV carriers" might be able to satisfactorily react to
the turnover of the quasi species, avoiding the escape mechanism.
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.
indifferent HCV genotype distribution together with the lack of association of
any particular HCV 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 HCV might be mainly determined by a more or less aggressive HCV
initial screening of anti-HCV-positive patients, we recognized 2 patients who
were HCV RNA negative and who had normal liver histology. These patients never
showed positivity for HCV RNA. They might have recovered from the acute disease
showing a permanent immunity (anti-HCV positive). One patient who was
persistently positive for HCV RNA also had no signs of liver disease at biopsy,
thus confirming that true "healthy carriers" of HCV may exist. In
conclusion, this study suggests that the majority of asymptomatic carriers of
anti-HCV 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-HCV carriers, along with
subjects with chronic hepatitis and HCV healthy carriers, may represent subjects
who healed after HCV 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
histological, and virological features of hepatitis C virus carriers with
persistently normal or abnormal alanine transaminase levels
Magrini A, Stati T, Rigato P, Montagnese F, Rossi P, Aldegheri L and Resta S
Hepatology, Vol 26, 1393-1398
study was aimed to evaluate demographic, clinical, histological, and virological
characteristics of 46 hepatitis C virus (HCV) carriers with persistently normal
alanine transaminase (ALT) levels and to compare the results with those obtained
in a group of 52 HCV-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 HCV
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. HCV 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 HCV-RNA titers than subjects with raised ALT. Neither HCV 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, HCV genotypes, and viral load.
Alfa Treatment of HCV RNA Carriers With Persistently
Transaminase Levels: A Pilot Randomized Controlled Study
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
patients with serum hepatitis C virus (HCV) 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 HCV suppression in these
patients, 31 previously untreated patients (15 men, 16 women; mean age, 44
years) with serum HCV 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.
HCV 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 HCV core region. Treated and
untreated patients had similar epidemiological, virological, and histological
characteristics. At the end of treatment, serum HCV 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 HCV 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 HCV RNA
carriers with normal ALT levels, these patients should not be treated with IFN.
Progression Rate of Fibrosis in Hepatitis C Virus Patients With
Normal Alanine Transaminase Activity
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 (HCV) patients with persistently normal alanine transaminase (ALT), the progression rate of fibrosis is unknown. The aims of this study were: 1) to compare HCV patients with normal ALT (group I) with HCV 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 HCV 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). HCV 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 HCV-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. HCV patients with normal ALT showed weaker histological activity and lower fibrosis scores, and the progression rate of fibrosis was twice as slow as in HCV patients with elevated ALT. In these patients, severe fibrosis was associated with high alcohol consumption.