This 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.

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 (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.

Introduction:

Many 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.

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-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 interferon treatment.

Discussion:

Most 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).

This 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

selected 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.

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 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.

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 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 genotype.

Through 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 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 (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.  

(14) Interferon Alfa Treatment of HCV 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 (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.

(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 (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.