Gastroenterology

Gastroenterology

Volume 138, Issue 3, March 2010, Pages 1123-1133.e3
Gastroenterology

Basic—Liver, Pancreas, and Biliary Tract
Cell-Type Specific Gene Expression Signature in Liver Underlies Response to Interferon Therapy in Chronic Hepatitis C Infection

https://doi.org/10.1053/j.gastro.2009.10.046Get rights and content

Background & Aims

Chronic hepatitis C virus (CHC) infection is treated with interferon/ribavirin, but only a subset of patients respond. Treatment nonresponders have marked pretreatment up-regulation of a subset of interferon stimulated genes (ISGs) in their livers, including ISG15. We here study how the nonresponder gene expression phenotype is influenced by clinical factors and uncover the cellular basis of the phenotype through ISG15 protein expression.

Methods

Seventy-eight CHC patients undergoing treatment were classified by clinical (gender, viral genotype, viral load, treatment outcome) and histologic (inflammation, fibrosis) factors and subjected to gene expression profiling on their pretreatment liver biopsies. An analysis of variance model was used to study the influence of individual factors on gene expression. ISG15 immunohistochemistry was performed on a subset of 31 liver biopsy specimens.

Results

One hundred twenty-three genes were differentially expressed in the 78 CHC livers when compared with 20 normal livers (P < .001; fold change, ≥1.5-fold). Of genes influenced by a single factor, genotype (1 vs 2/3) influenced more genes (17) than any other variable; when treatment outcome was included in the analysis, this became the predominant influence (24 genes), and the effect of genotype was diminished. Treatment response was linked to cell-specific activation patterns: ISG15 protein up-regulation was more pronounced in hepatocytes in treatment nonresponders but in Kuppfer cells in responders.

Conclusions

Genotype is a surrogate marker for the nonresponder phenotype. This phenotype manifests as differential gene expression and is driven by activation of different cell types: hepatocytes in treatment nonresponders and macrophages in treatment responders.

Section snippets

Chronic HCV

Seventy-eight patients with CHC (56 genotype 1, 22 genotype non-1) were treated at University Health Network from October 2001 through May 2004. All patients underwent pretreatment percutaneous liver biopsy and had baseline viral loads determined. Treatment was either PegIFN2a 180 μg or PegIFN2b 1.5 μg/kg subcutaneously weekly and oral ribavirin 800–1200 mg daily for 24 (genotypes 2/3) or 48 (genotypes 1, 4, and 6) weeks. Quantitative HCV-RNA was determined at completion of therapy and 6 months

Patient Demographics

Demographic and clinical variable data on the 78 CHC patients are summarized in Table 1. The majority (72%) was infected with HCV genotype 1. Patients were denoted “low fibrosis” if their Ishak scores were 0–2 and “high fibrosis” if their scores were 3 or 4.27 Similarly, patients were classified “low activity” if their METAVIR A scores were 0–2 and “high activity” for scores of 3 or 4. For this study, high viral load was defined as >8 × 106 IU/mL. Comparing genotype 1 and non-1 patients, there

Discussion

Although the molecular mechanisms involved in IFN resistance in CHC patients who do not respond to treatment are not well understood, the interaction between viral and host factors plays a critical role. In this study, we present evidence that chronic infection with HCV leads to 2 different states at the level of hepatic gene and protein expression: one, the “high ISG” NR phenotype, is associated with high level ISG expression in hepatocytes; the other, the “low ISG” R phenotype, has more ISG

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    Conflicts of interest The authors disclose no conficts.

    Funding Supported by grants from the Canadian Institute of Health Research (No. 62488; to I.D.M), by the National Canadian Research Training Program in Hepatitis C (NCRTP-HepC; to L.C. and I.B.), and by a Canada Graduate Scholarship (CGS) from the Canadian Institute of Health Research (to L.C.).

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