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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
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.
Department of Infectious Diseases and Pathology
IRCCS Policlinico San Matteo
University of Pavia
Pavia, Italy
GASTROENTEROLOGY 2000;118:760-764
Natural History of Hepatitis C Virus Carriers With Persistently Normal Aminotransferase Levels
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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