Updated thresholds for alanine aminotransferase do not exclude significant histological disease in chronic hepatitis C.

Background and aim: Histological changes in hepatitis C virus (HCV)infected patients with persistently normal alanine aminotransferase (PNALT) have not been evaluated for updated upper limits of normal (ULN; 19/30 U/L for females/males). We assessed significant fibrosis (ZF2, METAVIR) in patients with PNALT and persistently elevated alanine aminotransferase (PEALT). Patients and methods: Nine hundred and twenty consecutive, unselected HCV patients were stratified into four groups: Group I: (n=124) PNALT within the updated ULN [0.5ULN (corresponding to 19U/L) for females; 0.75ULN (corresponding to 30U/L) for males]; Group II (n=173): PNALT 1ULN but greater than Group I; Group III (n=313): PEALT 1‐2ULN; and Group IV (n=310): PEALT42ULN. PNALTwas defined as Z3 determinations within the normal range over Z6 months. Results: Advanced ZF3 and ZF2 fibrosis increased incrementally across Groups I; II; III; and IV: 24.2 and 45.2%; 25.4 and 56.1%; 36.1 and 64.2%; and 50 and 77.1% respectively (Po0.0001 for both). Multivariable logistic regression analysis identified age [odds ratio (OR), 1.05; 95% confidence intervals (CI): 1.02‐1.08; Po0.0001], alanine aminotransferase (ALT) groups (OR 1.38; 95% CI: 1.03‐1.83; P=0.030), presence of moderate‐severe steatosis (OR 2.70; 95% CI: 1.19‐6.15; P=0.018) and ZA2 necroinflammation (OR 17.9; 95% CI: 8.88‐36.20; Po0.0001) as independent predictors of ZF2 fibrosis. Updated ULN for ALT were better at excluding ZF2 fibrosis compared with traditional ULN (90.6 vs. 74.2%, P=0.0041) but less specific (20.8 vs. 44%, P=0.0007) with similar positive/negative predictive values. Conclusions: HCV patients with ‘updated’ normal ALT have the lowest prevalence of significant fibrosis, although utilizing these levels without resorting to biopsy would miss significant fibrosis in almost one-half of such patients. The risk of progression of hepatitis C virus (HCV) infection to chronicity is in the range of 70‐85%, and about 20% of patients with chronic HCV progress to cirrhosis (1). Most patients with chronic HCV have elevated or fluctuating levels of serum alanine aminotransferase (ALT), and commonly exhibit histological evidence of active inflammation and fibrosis (2, 3). The value of elevated ALT levels in predicting inflammatory activity and fibrosis is well established; however, much debate exists in the approximately 25‐46% of HCVinfected patients with persistently normal alanine aminotransferase (PNALT) levels (4‐7). Reports suggest that patients with PNALT have mild inflammatory activity and slow progression of fibrosis (7‐9). Previously, investigators have utilized arbitrary ALT levels ranging from less than the upper limit of normal