Micro-RNA-122 levels in acute liver failure and chronic hepatitis C

Abstract

MicroRNA-122 (miR-122) is the foremost liver-related micro-RNA, but its role in the hepatocyte is not fully understood. To evaluate whether circulating levels of miR-122 are elevated in chronic-HCV for a reason other than hepatic injury, we compared serum level in patients with chronic hepatitis C to other forms of liver injury including patients with acute liver failure and healthy controls. MiR-122 was quantitated using sera from 35 acute liver failure patients (20 acetaminophen-induced, 15 other etiologies), 39 chronic-HCV patients and 12 controls. In parallel, human genomic DNA (hgDNA) levels were measured to reflect quantitatively the extent of hepatic necrosis. Additionally, six HIV-HCV co-infected patients, who achieved viral clearance after undergoing therapy with interferon and ribavirin, had serial sera miR-122 and hgDNA levels measured before and throughout treatment. Serum miR-122 levels were elevated approximately 100-fold in both acute liver failure and chronic-HCV sera as compared to controls (P < 0.001), whereas hgDNA levels were only elevated in acute liver failure patients as compared to both chronic-HCV and controls (P < 0.001). Subgroup analysis showed that chronic-HCV sera with normal aminotransferase levels showed elevated miR-122 despite low levels of hepatocyte necrosis. All successfully treated HCV patients showed a significant Log10 decrease in miR-122 levels ranging from 0.16 to 1.46, after sustained viral response. Chronic-HCV patients have very elevated serum miR-122 levels in the range of most patients with severe hepatic injury leading to acute liver failure. Eradication of HCV was associated with decreased miR-122 but not hgDNA. An additional mechanism besides hepatic injury may be active in chronic-HCV to explain the exaggerated circulating levels of miR-122 observed.

Keywords: HCV; acetaminophen; biomarker; liver injury; micro-RNA.

© 2014 Wiley Periodicals, Inc.

Figures

Fig. 1

Serum miR-122 and hgDNA levels across groups and subgroups. Values have been transformed using Log10. A: Three main study groups. B: Five subgroups. Plots presented using Tukey method. hgDNA, human genomic DNA; ALT, alanine aminotransferase; miR-122, microRNA-122.

Fig. 2

Relationship of serum miR-122 levels with serum ALT levels. ALT versus miR-122 levels using Log10 scale. Spearman rank order correlation for all cases was significant (rho = 0.481, P<0.001). Only the subgroups Elevated-chronic hepatitis C (rho = 0.621, P = 0.002) and Normal-chronic hepatitis C (rho = 0.620, P = 0.018) were significantly correlated with ALT. ALT levels were not available for healthy controls.

Fig. 3

Relationship of serum hgDNA levels with serum ALT levels. ALT versus hgDNA levels using Log10 scale. Spearman rank order correlation for all cases was significant (rho = 0.622, P<0.001). No subgroups were significantly correlated with ALT levels. ALT levels were not available for healthy controls.

Fig. 4

Serial miR-122 and hgDNA values across treatment time points for patients undergoing hepatitis C treatment. A: Log miR-122 levels across treatment time points. Median values decrease following Week 1, and are significantly lower at sustained viral response. B: Serial Log10 hgDNA levels across treatment time points. No significant differences were observed in hgDNA levels. Plots presented using Tukey method.