Abstract
MicroRNAs miR-122, miR-34a, miR-16 and miR-21 are commonly deregulated in liver fibrosis and hepatocellular carcinoma. This study examined whether circulating levels of these miRNAs correlate with hepatic histological disease severity in patients with chronic hepatitis C infection (CHC) or non-alcoholic fatty-liver disease (NAFLD) and can potentially serve as circulating markers for disease stage assessment. We first used an in vitro model of hepatitis C virus (HCV) infection to measure the extracellular levels of these four miRNAs. Whereas miR-21 extracellular levels were unchanged, extracellular levels of miR-122, miR-34a and to a lesser extent miR-16, steadily increased during the course of HCV infection, independently of viral replication and production. Similarly, in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher than in control individuals, while miR-21 levels were unchanged. There was no correlation between the serum levels of any of these microRNAs and HCV viral loads. In contrast, miR-122 and miR-34a levels positively correlated with disease severity. Identical results were obtained in an independent cohort of CHC patients. We extended the study to patients with NAFLD. As observed in CHC patients, serum levels of miR-122, miR-34a and miR-16 were significantly higher in NAFLD patients than in controls, while miR-21 levels were unchanged. Again, miR-122 and miR-34a levels positively correlated with disease severity from simple steatosis to steatohepatitis. In both CHC and NAFLD patient groups, serum levels of miR-122 and miR-34a correlated with liver enzymes levels, fibrosis stage and inflammation activity. miR-122 levels also correlated with serum lipids in NAFLD patients. Conclusion: Serum levels of miR-34a and miR-122 may represent novel, noninvasive biomarkers of diagnosis and histological disease severity in patients with CHC or NAFLD.
Highlights
Liver biopsy is often recommended in patients with unexplained elevated serum aminotransferases in order to determine the cause, to stage hepatic fibrosis and to grade hepatic inflammation
This study examined whether serum levels of selected miRNAs, thought to be deregulated in liver disease, can serve as noninvasive biomarkers of diagnosis and histological severity in patients with chronic hepatitis C (CHC) or non-alcoholic fatty liver disease (NAFLD)
At 10 days postinfection, corresponding to the highest levels of hepatitis C virus (HCV) RNA, extracellular levels of miR-122 and miR-16 increased by 3.3-fold and 2.1-fold, respectively, while miR-21 remained unchanged. miR-34a levels were undetectable in supernatant of uninfected Huh7.5 cells as well as in cells infected with HCV for 5 days, but increased to detectable levels at 10 days post-infection
Summary
Liver biopsy is often recommended in patients with unexplained elevated serum aminotransferases in order to determine the cause, to stage hepatic fibrosis and to grade hepatic inflammation. Noninvasive methods that can evaluate disease severity and the likelihood of disease progression in persons with elevated liver enzymes need to be developed. MicroRNAs are small non-coding RNAs that control translation and transcription of many genes. They are receiving growing attention because of numerous reports on their dysregulation in human diseases and their potential as diagnostic and therapeutic targets. Numerous studies have shown that aberrant miRNA expression is associated with the development and progression of various types of human cancer and studies on circulating miRNA profiles largely focused on cancer [1,2,3]
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