Abstract
Circulating microRNAs have been widely recognized as a novel category of biomarker in a variety of physiological and pathological conditions. Other reports revealed that fragments of organ specific messenger RNAs are also detectable in serum/plasma and can be utilized as sensitive indicators of liver pathology and cancer. In order to assess the sensitivity and reliability of these two class of RNAs as marker of hepatitis B or C induced chronic liver disease, we collected plasma samples from 156 chronic hepatitis B or C patients (HBV active n = 112, HBV carrier n = 19, hepatitis C n = 25) and 22 healthy donors and quantified their circulating mRNA for albumin, HP (haptoglobin), CYP2E1 (cytochrome P450, family 2, subfamily E) and ApoA2 (Apolipoprotein A2) in conjunction with microRNA-122, a well established marker for acute and chronic liver injury. We found that plasma microRNA-122 level is significantly elevated in patients with active HBV but not in HBV carriers. Furthermore, microRNA-122 is not elevated in HCV patients even though their median serum alanine aminotransferase (sALT) was three fold of the healthy donors. Nevertheless, circulating mRNAs, especially albumin mRNA, showed much more sensitivity in distinguishing active hepatitis B, hepatitis B carrier or HCV patientsfrom healthy control. Correlation and multiple linear regression analysis suggested that circulating mRNAs and miRNAs are much more related to HBsAg titre than to sALT. Immunoprecipitation of HBsAg in HBV patients’ plasma resulted in enrichment of albumin and HP mRNA suggesting that fragments of liver specific transcripts can be encapsidated into HBsAg particles. Taken together, our results suggest that hepatocyte specific transcripts in plasma like albumin mRNA showed greater sensitivity and specificity in differentiating HBV or HCV induced chronic liver disease than microRNA-122. Circulating mRNA fragments merit more attention in the quest of next generation biomarkers for various maladies.
Highlights
Circulating nucleic acids in human peripheral blood has been increasingly acknowledged as indicators for a variety of physiological and pathological conditions including liver injury induced by hepatotoxic agents and viral hepatitis [1]
Fragments of messenger RNAs in plasma/serum were found to reflect acute liver injury caused by hepatotoxic compounds [6,7] and liver pathologies induced by hepatitis B virus [8]
We quantified the abundance of messenger RNAs for albumin, HP, CYP2E1 and APOA2 mRNA in conjunction with miRNA122 in 131 HBV, 25 HCV patients and 22 healthy donors by qRT-PCR. miRNA-122 was chosen as miRNA marker for liver disease because it is highly abundant in hepatocytes and is repeatedly reported to reflect liver damage [2,3]
Summary
Circulating nucleic acids in human peripheral blood has been increasingly acknowledged as indicators for a variety of physiological and pathological conditions including liver injury induced by hepatotoxic agents and viral hepatitis [1]. Quite a number of reports asserted that plasma miRNAs are excellent indicators for diseases ranging from acute liver injury [2,3] to various malignancies [4,5]. Fragments of messenger RNAs in plasma/serum were found to reflect acute liver injury caused by hepatotoxic compounds [6,7] and liver pathologies induced by hepatitis B virus [8]. For microRNA, miRNA-122 was selected since it has been independently confirmed as a reliable indicator for liver injury caused by hepatoxic agents [2,3] and hepatitis B virus [9,10]. We included transcripts for CYP2E1 (cytochrome P450, family 2, subfamily E), APOA2 (Apolipoprotein A2) and HP (haptoglobin) based on their tissue specificity and high abundance in hepatocytes
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