Histological features and HLA class II alleles in hepatitis C virus chronically infected patients with persistently normal alanine aminotransferase levels. (Liver Disease).

Objective: A significant proportion of individuals with chronic hepatitis C virus (HCV) infection hove persistently normal alanine aminotransferase (ALT) levels. Although data are controversial, such patients usually have weaker histological damage and a lower progression rate of fibrosis. The aims of this study were: (1) to compare demographic, virological, and histological parameters of HCV patients with normal ALT values with those of HCV patients with elevated ALT levels; and (2) to determine whether HLA class II alleles contribute to the persistence of normal ALT levels in HCV patients.

Patients and methods: Eighty three patients with chronic HCV infection and persistently normal ALT values (group 1) and 233 patients with chronic HCV infection and elevated ALT levels (group 2) were studied. Histological features were expressed using Knodell and Metavir scores. HLA DRB1 * and DQB1 * genotyping was performed using hybridisation with sequence specific oligonucleotides after genomic amplification. The [chi square] and Fisher's exact tests were used to compare discrete variables and phenotype frequencies between the two groups, and Wilcoxon's test was used for continuous variables. A multivariate logistic regression model was used to determine which variables predicted normal ALT values.

Results: ALT levels were correlated with the severity of liver damage. In group 1, 93% of patients had an F0 or F1 Metavir index of fibrosis compared with 47% of patients in group 2 (p<0.001). A longer duration of infection (p<0.001) and increased DRB1*11 phenotype frequency (pc=0.03) were observed among patients with normal ALT. The two groups did not differ with regard to the mode of contamination or viral genotype. After logistic regression, young age (p=0.0008), female sex (p=0.01), long duration of infection (p=0.0001), and HLA DRB1*11 (p=0.050) were more strongly associated with persistence of normal ALT.

Conclusions: Our study confirms that patients with chronic hepatitis C and normal ALT levels have less severe liver disease than those with elevated ALT levels. This particular biochemical outcome may be explained, at least in part, by host immunagenetic factors such as the presence of HLA-DRB1*11.

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Elevated alanine aminotransferase (ALT) levels characterise chronic hepatitis C virus (HCV RNA positive) but a substantial proportion of chronically infected patients have normal ALT levels. (1) Subjects with active HCV replication and repeatedly normal ALT values represent approximately 25% of blood donors who are found to be anti-HCV positive on routine testing. (2 3)

The natural course of HCV infection in patients with persistent normal ALT levels is not well understood. Data concerning the histological characteristics of these patients are controversial. While some studies did not find any relationship between ALT levels and histological features, (4 5) recent reports indicate that patients with normal ALT values usually have milder liver disease that progresses more slowly than patients with elevated ALT. (6 7) Whether a specific mechanism of liver damage induced by HCV is responsible for this unusual disease profile is unclear. Viral factors such as viral load, (4 6 8) HCV genotype, (5-8) or quasispecies variability (8 9) do not seem to be associated with ALT levels. Alternatively, the host immune response directed to HCV infected cells may be involved in the pathogenesis of HCV infection with normal ALT.

Major histocompatibility complex (MHC) alleles have been shown to influence the outcome of HCV infection. Self limiting HCV infection and persistent HGV infection are commonly associated with different HLA class II alleles which confer susceptibility or resistance to viral clearance or persistence. (0-15) Few studies however have examined the relationship between HLA class II genotypes and ALT levels in chronically HCV infected patients. (15-18)

The aims of the present study were: (1) to evaluate demographic, virological, and histological features of chronically HCV infected patients with normal ALT; (2) to compare these parameters with those of chronically HCV infected patients with elevated ALT levels; and (3) to compare the distribution of HLA class II alleles in these two patient groups in order to establish whether the host immunogenetic factors influence this particular biochemical course of chronic HCV infection.

PATIENTS AND METHODS

Patients

A total of 316 HCV positive patients were studied. They were divided into two groups. Group 1 consisted of 83 consecutive chronically HCV infected patients with persistently normal ALT levels (36 men and 47 women; mean age 44.5 years (range 22-79)). All were Caucasians living in France and were prospectively recruited from hepatogastroenterology and internal medicine departments of 17 French hospitals between January 1999 and June 2000. All 83 patients had detectable serum HCV RNA by polymerase chain reaction (PCR). ALT normality was tested on at least five consecutive samples over a period of six consecutive months. In addition, because fluctuating ALT levels characterise chronic hepatitis C, the presence of an abnormal ALT value before this evaluation led to exclusion of the patient. Patients with hepatitis B surface antigen positivity, human immunodeficiency virus infection, alcohol consumption greater than 40 g/day for men and 20 g/day for women, other causes of chronic liver disease, or previous interfer on and/or ribavirin therapy were excluded from the study. After enrolment in the study, patients underwent a physical examination, ultrasound liver evaluation, and percutaneous liver biopsy.

Group 2 consisted of …