Hepatitis C Virus-infected Patients with a Persistently Normal Alanine Aminotransferase: Do They Exist and is this Really a Group with Mild Disease?

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Hepatitis C Virus-infected Patients with a Persistently Normal Alanine Aminotransferase: Do They Exist and is this Really a Group with Mild Disease?

Abstract

Opinion varies on whether or not hepatitis C virus (HCV) infected patients with persistently normal aminotransferase (PNALT) levels represent a group with mild disease. To evaluate the risk of ALT flare and fibrosis progression in patients with PNALT followed up as part of the Trent HCV cohort. Treatment-naïve patients with an elevated ALT (n = 1140) or PNALT, the latter defined as either an ALT ≤ 30 IU/L (n = 43) or an ALT ≤ 40 IU/L (n = 87) on ≥2 occasions in the 6 months following diagnosis, and no ALT > 40 U/L were included. The likelihood of maintaining a PNALT ≤ 30 IU/L was 42.2% and PNALT ≤ 40 IU/L 41.7% at 3 years. The Ishak fibrosis score was ≥3 in 3.7%, 8.3% and 29.6% of patients with PNALT ≤ 30 IU/L, PNALT ≤ 40 IU/L and elevated ALT, respectively. Fibrosis progression between paired biopsies was similar for patients with PNALT ≤ 30 IU/L (0.33 ± 0.94 Ishak fibrosis points/year), PNALT ≤

40 IU/L (0.35 ± 0.82) and elevated ALT (0.19 ± 0.48). The majority of those defined as PNALT subsequently have an abnormal ALT. They have a similar risk of disease progression to other HCV infected patients and, therefore, warrant the same consideration with regard to treatment.

Introduction

Alanine aminotransferase (ALT) is a frequently used serum marker of liver injury. Evidence from data on volunteer blood donors, however, suggests that 20–40% of hepatitis C virus (HCV) RNA positive patients will have a normal ALT level at the time of diagnosis.[1–3] A proportion of these patients will have a persistently normal ALT (PNALT), usually defined as two or three consecutive measurements within the normal range over a 6-month period.[4,5] There is conflicting evidence, however, on whether these patients represent a subgroup with mild disease and at low risk of disease progression.[6–9] There is also controversy on what constitutes a normal ALT, with good evidence to suggest that a threshold of 40 IU/L fails to

identify some patients with significant liver disease.[10]

There is good reason, therefore, for having a better understanding of the natural history of patients with PNALT, as knowledge of disease progression will help aid decisions with regard to therapy. The aim of this study, therefore, was to evaluate the risk of ALT flare and fibrosis progression in a cohort of HCV infected patients with PNALT, followed up longitudinally as part of the Trent HCV cohort study. Both 40 IU/L and the lower threshold of 30 IU/L were used to define a PNALT.

Patients and Methods

The Trent HCV cohort study was established in 1991 with the aim of studying the epidemiology and natural history of HCV infection in a defined and representative area of the UK (Trent Health Care region: population 5.1 million, from which the majority of individuals diagnosed with HCV infection will be referred to one of the participating clinics). The Trent HCV Cohort study has approval from a Multi-centre Research Ethics Committee.

Patients are enrolled in the Trent HCV Cohort study after informed consent. Risk factor data are categorised hierarchically as (1) injecting drug use, (2) receipt of blood (pre-1991) or blood product (pre-1986) transfusion, (3) other risk factor (born abroad, non-professional tattoo, professional tattoo prior to 1982), (4) none of the above risk factors, and (5) risk factor data missing. Duration of infection is estimated on the assumption that infection was acquired at the first exposure to risk. Information is also collected on past alcohol consumption at enrolment to the cohort and subsequently on alcohol consumption over the week prior to each clinic attendance. Patients with known human immunodeficiency virus infection or inherited coagulation disorders are identifiable within the cohort but excluded from analysis as the natural history may differ in these groups. All other patients with HCV are included in the analysis, including those known

to have advanced liver disease at diagnosis.

Patients are also flagged with the National Health Service Central Register. This identifies deaths, cancer registrations and emigrations and forwards the information regularly to the study group.

Study Population

The Trent HCV study cohort includes 2184 HCV RNA positive patients for which there are over 27 000 separate ALT measurements recorded on the database. Laboratory data, including ALT is regularly downloaded from each centre's pathology database. All laboratories used in the study have an upper limit of normal for ALT of 40 IU/L. For this study we included all treatment-naïve patients and divided them according to whether they had either an elevated ALT, defined as at least one ALT > 40 IU/L in the 6 months following diagnosis (n = 1140) or a PNALT. Two definitions of PNALT were used, either an ALT ≤ 30 IU/L (n = 43) or an ALT ≤ 40 IU/L (n = 87) on two or more occasions (at least 1 month apart) in the 6 months following diagnosis. Patients with a PNALT ≤ 30 IU/L will by definition also be included in the PNALT ≤ 40 IU/L group.

Follow-up

Entry into the study was defined as the date on which the patient was diagnosed with HCV. Follow-up for this study was until the date of death or transplantation, last recorded clinic visit or initiation of antiviral therapy. ALT measurement and liver biopsy were performed as part of routine clinical care and the latter was scored by a histopathologist at each participating centre using the Ishak disease severity score.[11] The agreed management protocol for patients within the Trent study recommended repeat liver biopsy at 2 yearly intervals for patients not treated after the initial biopsy. The likelihood of the ALT remaining normal in PNALT patients was assessed by scrutiny of ALT values taken after the initial 6 months definition period for PNALT. Liver histology was considered for analysis when the first biopsy was within 1 year of diagnosis

[PNALT ≤ 30 IU/L: 28/43 (65%), PNALT ≤ 40 IU/L: 59/87 (68%) and elevated ALT: 628/1140 (55%)]. Fibrosis progression in those patients with paired biopsies [PNALT ≤ 30 IU/L: n = 11 (26%), PNALT ≤ 40 IU/L: n = 15 (17%), elevated ALT: n = 164 (14%)] was expressed as Ishak fibrosis points per year. Patients with cirrhosis (Ishak stage 6) on the initial biopsy, and who could not therefore progress, were excluded from this analysis, as were patients who received antiviral therapy between the two biopsies